Indonesj 178 Gunardi Obstet GynecoJ

I EDITORIAL I Family Planning Problem in Indonesia

Eka R Gunardi

According to the world population data sheet in 2015, Indonesia was the 4th largest population country in ~he world with 256 million people.1 By total fertility rate 2.6, there will be 310 millions of Indonesian people in 2035. Large population represents serious threat, as over-population is the root of environmental problems, such as unsanitary living conditions, the depletion of resources, environmental pollution, and also poverty. One ofthe prerequisites for improving Indonesian people's quality ofHfe is through balancing the population growth by controlling the quantity of population. One of the ways is through family planning. Stated at Act No. 52 of 2009 on population and family development, the family construction is the foundation to create the quality family who lives in a healthy environment2 This law supports family planning program as a part of efforts to control the pregnancy by using contraceptives. There are some problems in family planning program. Firstly, the contraceptive prevalence rate did not increase significantly from 60.3% in 2002 to 61.4% in 2007. It remained constant to 61.9% in 2012. Secondly, the total fertility rate (TFR) in same period is only slightly decreased from 3.0 to 2.6. Among ASEAN countries, Indonesia ranked the number six for the lowest fertility rates. Therefore, we still need more effort to earn better result in family planning program.3 The reason behind thiS phenomenon is the use of Non-LTCM (Long·Term Contraception Method) higher than LTCM. Non·LTCM, which has a duration of 1-3 months, shows higher dropout rate (25-41%). Long Term Contraceptive Method ranging from 3 to 5 years of use provides higher chance for survival; however, the number of users are lower than Non·LTCM. This may be caused because the use of this method requires more complex action and skills of health professionals.4 Long-term contraception method (LTCM), such as IUD and Implant can be used for the spouse of fertile age that planned to delay the pregnancy; meanwhile, sterilization is used for spouse who planned to stop the fertility,S Implant is a contraceptive containing Levonorgestrel wrapped in capsules silastic silicone (polidemtsilixane) and implanted under the skin. Implant has long service life, release stable low dose hormone, and has reversible effect for the women fertility, The successful rate of this implant contraceptive is high, nearly 100%.5 There are some types of implant contraception that available in Indonesia, those are Norplant that has six small silicone rods, Jadelle or Indoplant that has two rods. However, study about effectiveness between those types of implant in Indonesia is still not available. Therefore, in this edition, we try to compare the effectiveness of 2 and 6 rods of implant as contraceptive methods.

References

1. World Population Data Sheet. Jakarta: Population Reference Bureau, 2015. 2. Kementerian Hukum dan Hak Asasi Manusia Repubtik Indonesia. Undang-undang Republik Indonesia No. 52 tahun 2009 tentang perkembangan kependudukan dan pembangunan keluarga. 2009. 3. Jones G. The 2010 - 2035 Indonesian Population Projection Understanding the Causes, Consequences and Policy Options for Population and Development. United Nations Population Funds, 2016. 4. Badan Kependudukan dan Keluarga Berencana Nasional. Survey Demografi dan Kesehatan Indonesia 2012, August 2013. S. Saifuddin AB, Affandi B. Kontrasepsi. In: Wiknjosastro H, Saifuddin AB, Rachimhadhi T. Ilmu Kebidanan 3nl ed. Jakarta: Yayasan Bina Pustaka Sarwono Prawirohardjo; 2007: 905-33. Vol 4, No 4 October 2016 Characteristics of preeclampsia with severe features 179

Research Article

The Characteristics of Preeclampsia with Severe Features Karakteristik Preeklamsia dengan Tanda Perburukan

JM Seno Adjie, Fredy Lisnan, Yosep Sutandar Department of Obstetrics and Gynecology Faculty of Medicine Universitas Indonesia/ Dr. Cipto Mangunkusumo Hospital Jakarta

Abstract Abstrak

Objective: To describe the characteristics of preeclampsia with se- Tujuan: Untuk mendeskripsikan karakteristik preeklamsia dengan vere features and their risk factors. tanda perburukan dan faktor risikonya. Method: This study was a retrospective medical record review of Metode: Penelitian ini merupakan penelitian retrospektif mengenai demographic characteristics, obstetric and medical data of pree- karakteristik preeklamsia dengan tanda perburukan pasien-pasien clampsia with severe features in Dr. Cipto Mangunkusumo Hospital obstetri dan ginekologi di RS Dr. Cipto Mangunkusumo dari bulan Juli 2014 sampai Desember 2014. from July to December 2014. Hasil: Terdapat 1013 total persalinan selama studi dilakukan, dan di Result: There were 1,013 deliveries which 183 patients of them antaranya terdapat 183 (18,06%) kasus preeklamsia dengan tanda were diagnosed as preeclampsia with severe features (18.06%). The perburukan. Dari penelitian ini didapatkan 67,76% pasien berada di study showed 67.76% were 20 - 35 years old, most of them were rentang umur 20-35 tahun dan mayoritas dari pasien tersebut adalah multiparity, and 41.53% were preterm labor with 28 - 336 weeks of multiparitas; dan 41,53% adalah persalinan preterm pada 28-336 gestation then followed by 24.59% were 34 - 366 weeks’ gestation. minggu gestasi dan diikuti 24,59% persalinan preterm pada 34-366 Majorities of preeclampsia with severe features patients were with- minggu gestasi. Mayoritas pasien dengan preeklamsia dengan tanda out complication either to the mother or the baby. There were 1 case perburukan tidak mengalami komplikasi, baik pada ibu maupun ba- yinya. Didapatkan pula 1 kematian maternal dan 15 kematian fetus of maternal mortality and 15 cases of intra uterine fetal death dalam rahim. Terdapat sekitar 73,77% kasus yang dilahirkan melalui (IUFD). There were 73.77% cases delivering by cesarean section. seksio sesarea. Preeklamsia dengan tanda perburukan dengan kom- The complication of the mother in preeclampsia with severe fea- plikasi secara signifikan berhubungan dengan persalinan preterm. Se- tures was related significantly to the complication in baby, such as lain itu, usia maternal dan status paritas dengan preeklamsia dengan preterm delivery. Besides, women’s age and parity had significant tanda perburukan dan komplikasi terhadap bayi. relationship with baby complication. Kesimpulan: Preeklamsia dengan tanda perburukan dengan kompli- Conclusion: There is association of complication in preeclampsia kasi secara signifikan berhubungan dengan persalinan preterm. Selain with severe features women with baby, namely preterm delivery. itu, umur maternal dan status paritas secara siginifikan berhubungan dengan preeklamsia dengan tanda perburukan dan komplikasi ter- Besides, women’s age and parity is related to complication of baby. hadap bayi. [Indones J Obstet Gynecol 2016; 4-4: 179-182] [Maj Obstet Ginekol Indones 2016; 4-4: 179-182] Keywords: complication, preeclampsia, risk factors Kata kunci: faktor risiko, komplikasi, perburukan, preeklamsia

Correspondence: JM Seno Adjie, [email protected]

INTRODUCTION Preeclampsia is defined as a syndrome consisting of hypertension with blood pressure more or equal Maternal mortality is a health indicator which de- to 140/90 and/or proteinuria more or equal to scribes the condition of its country. It shows the positive 1. These signs are appeared at 20 weeks very wide gap between rich and poor, urban and of gestational age and resolved at 12-week post- rural areas among countries in the world. World partum. While, preeclampsia with severe features Health Organization (WHO) attempts to reduce the is known as hypertension with blood pressure maternal mortality rate (MMR) around the worlds, more or equal to 160/110 and/or proteinuria including Indonesia through Millennium Develop- more or equal to positive 2. The onset is similar to ment Goals (MDGs) continued by Sustainable De- preeclampsia. The risk factors for preeclampsia are velopment Goals (SDGs).1 Based on data from In- multifactorial. Several risk factors which have been donesia Department of Health, preeclampsia is one identified are molar pregnancies, nulliparity, aged of three commonest cause for maternal death.2 less than 20 years old or over 35 years old, more Indones J 180 Adjie et al Obstet Gynecol than one fetus, chronic hypertension, diabetes mel- The incidence of preeclampsia occurs on 5% litus and renal disease. Besides, preeclampsia is population of white women, 9% population of also influenced by parity, genetic, and environ- women Hispanic, 11% in women African-Ameri- mental factors.1,3 can. The incidence on nullipara reaches 3-10%, maternal weight affects the risk of preeclampsia The incidence of preeclampsia was relatively from 4.3 to 13.3%.6 Women with preeclampsia in stable between 4 and 5 cases per 10,000 live births their first pregnancy have a greater risk to be pree- in developed countries. In the developing coun- clampsia in the next pregnancy. Smoking during tries, the incidence of preeclampsia was around pregnancy is associated with reduced risk of hy- 3.9%. Meanwhile, in Dr. Cipto Mangunkusumo hos- pertension in pregnancy.6 Therefore, this study pital as the center of referral hospital in Indonesia, aims to describe the characteristics of preeclamp- the incidence in 2008-2009 was 16.3%.4 The MMR sia with severe features and their risk factors was varied from 0% to 4%. Increased maternal death due to complications involves various body systems, such as intracerebral hemorrhage and METHODS pulmonary edema. Preeclampsia has also an im- This study was a retrospective medical record re- pact for the baby ending to the infant death. The view about preeclampsia with severe features in perinatal mortality rate was ranged from 10% to Dr. Cipto Mangunkusumo Hospital. All preeclamp- 28%. Prematurity, growth retardation, and in- sia with severe features records between July and creased risk of abruption placenta often cause the December 2014 were collected and reviewed. We perinatal death. Approximately less than 75% did the statistical analysis using SPSS software. We eclampsia occurs antepartum and 25% in the post- used chi square to determine the relative risk partum. Almost all cases (95%) antepartum between several independent variables and fetal eclampsia are happened in the third trimester.5 complication.

Table 1. The Characteristics of Preeclampsia with Severe Features in Dr. Cipto Mangunkusumo Hospital Characteristics N % Age (years old) <20 10 5.46 20 - 35 124 67.76 >35 49 26.78 Parity <1 63 34.43 2 - 5 120 65.57 >5 0 0 Gestational Age (weeks) 20 - 276 84.37 28 - 336 52 28.42 34 - 366 45 24.59 37 - 416 76 41.53 >=42 2 1.09 Maternal Complication None 144 78.69 HELLP syndrome 27 14.75 Eclampsia 7 3.83 HELLP syndrome and Eclampsia 5 2.73 Fetal Complication None 151 82.52 IUGR 19 10.38 Poor APGAR score 10 5.46 IUGR and Poor APGAR score 3 1.64 Maternal Mortality Life 182 99.45 Dead 1 0.55 Fetal Mortality Life 168 91.80 Dead 15 8.20 Mode of Delivery Vaginal 48 26.23 Cesarean section 135 73.77 Vol 4, No 4 October 2016 Characteristics of preeclampsia with severe features 181 RESULTS teristics of less than 20 years old, primigravida, at term of gestation with HELLP syndrome and lung There were 183 cases of preeclampsia with severe edema. The baby was delivered by cesarean sec- features among 1,013 pregnant women recorded tion having poor APGAR score. Besides, there were coming to Dr. Cipto Mangunkusumo hospital at 15 intrauterine fetal death (IUFD) cases. Mean- Emergency Unit. The majority of preeclampsia with while, around 73.77% preeclamptic women with severe features cases was among 20-35 years old severe features were delivered by cesarean and multiparity (65.57%). Almost half of women section. (41.53%) were in term gestational age, followed by 28 - 366 weeks of gestation around 28.42%, and Table 2 showed that there was significant asso- 24.59% women was in 34 - 366 weeks of gestation. ciation between fetal and maternal complication of The majority of preeclampsia with severe features preeclampsia with severe features. cases had no complication either the mother or the Based on statistics, maternal age had significant baby; there were only 27 cases having HELLP syn- relationship with fetal complication; whereas, drome, 7 cases with eclampsia, and 5 cases with young maternal age (<20 years old) had a tendency both HELLP syndrome and eclampsia. In term of of increasing 2.2 times risk to have fetal complica- baby complication, only 17.48% baby were born tion (shown in Table 3). with complication consisting of intrauterine growth retardation (IUGR), poor APGAR score, Table 4 depicted that there was significant asso- IUGR and APGAR score in each percentage of ciation between parity and fetal complication; 10.38%, 5.46%, 1.46%; respectively. In this study, whereas, nulliparity was considered as the risk there was one maternal death with the charac- factor for the complication.

Table 2. Relationship between Fetal and Maternal Complication of Preeclampsia with Severe Features Fetal Maternal Complication Total RR CI 95% p­value With Complication Without Complication With 12 27 39 2.215 0.035-0.303 0.014 Without 20 124 144 1 Total 32 151 183

Table 3. Relationship between Fetal Complication and Maternal Age Fetal Maternal Age Total RR CI 95% p­value With Complication Without Complication < 20 years old 4 6 10 2.156 0.004-0.481 0.050 20 - 35 years old 23 101 124 1 > 35 years old 5 44 49 0.55 0.026-0.224 0.118 Total 32 151 183

Table 4. Relationship between Fetal Complication and Parity Fetal Parity Total RR CI 95% p­value With Complication Without Complication With 17 46 63 2.158 0.014-0.03 0.014 Without 15 105 120 1 Total 32 151 183 Indones J 182 Adjie et al Obstet Gynecol DISCUSSION features were HELLP syndrome (14.57%), eclampsia (3.82%) and both HELLP syndrome and eclampsia The number of preeclampsia with severe features (2.73%). Statistical analysis showed that preterm patients who came to Dr. Cipto Mangunkusumo pregnancy complication was related to the incidence hospital from July to December 2014 were 183 of preeclampsia with severe features. The analytic women of 1,013 pregnant women. The percentage issue was due to the lack of awareness for doing ANC, was around 18.06%. Compared with the period of poor economic society, and the number of children. 2008-2009 which was only 16.3%, it meant that In women with preeclampsia, the complication could there was an increasing around 2% within 5 years.4 be seen to the dominance of HELLP syndrome at It might be caused by the deterioration of the 28-336 weeks of gestation as much as 8.74% of the pregnant women’s health condition in Jakarta. total preeclampsia’s incidence. Apart from that, in the era of national health Preeclampsia caused one maternal death and 15 coverage (Jaminan Kesehatan Nasio-nal JKN), there IUFD in the second semester during 2014. Of the is an increasing awareness of people to seek IUFD cases, 12 cases were obtained in women with treatment at health center so that the number of preeclampsia without complications; while, compli- diagnosed case, especially preeclampsia raise in cation of preeclampsia with HELLP syndrome only hospital. caused one IUFD. Eclampsia and HELLP syndrome Of the characteristics, the dominance of women’s contributed to 2 patients with IUFD. In linear regres- age was between 20 and 35 years old (67.76%) and sion calculation, it was also found that there was no certainly, the number of maternal and fetal compli- association between complication of preeclampsia cation due to preeclampsia were dominant in that and IUFD. Maternal complication of preeclampsia age group, such as HELLP syndrome (70.37%), should not be associated with IUFD. Actually, IUFD eclampsia (85.71%), 80% for both eclampsia and itself was associated with the prematurity. HELLP syndrome. While, the fetal complication con- sisting of IUGR, poor APGAR score, IUGR with poor APGAR score was 73.68%, 60%, 100%; respectively CONCLUSION in the age group of 20-35 years old. Although mater- nal age was not significantly associated with compli- In Dr. Cipto Manggunkusumo Hospital, there are cation of preeclampsia with severe features, the 183 cases of preeclampsia with severe features women less than 20 years old had a tendency for among 1,013 patients that come to emergency unit complication of preeclampsia with severe features from July to December 2014. Preeclamptic women about 1.2 times greater than the maternal age of 20- with severe features are associated with preterm 35 years old. Besides, maternal age had a significant delivery. Apart from that, women’s age and parity relationship with fetal complication; whereas, have significant relationship with severe features women less than 20 years old tended to increase 2.2 preeclampsia and the complication of the baby. times of fetal complication. It is quite reasonable ac- cording to the habit in capital city, a lot of women postpone their pregnancy for the career. REFERENCES

Pregnancy in any parity group should be noticed 1. WHO. Millennium Development Goals: at a Glance 2010. to be preeclampsia. Based on statistical calculation, 2. Indonesia KKR. Profil Kesehatan Indonesia 2012. In: Supri- the result showed there was no association between natoro, Primadi O, Hardhana B, Budijanto D, Sitohang V, parity and maternal complications in preeclampsia, Soenardi TA, editors. Jakarta: Kementerian Kesehatan Re- although parity was related to fetal complication. publik Indonesia; 2013. This might occur due to other factors that have more 3. WHO. Mother-baby package: implementing safe mother- hood in countries 1994. (accessed 2014). influence on pregnant women than only a parity. 4. Kusuma T, Affandi B, Ocviyanti D, Prihartono J. Manajemen From the study, most of women were at term ges- risiko dalam pelayanan pasien preeklampsia berat (PEB)/ tational age. There were probably due to lack of eklampsia di instalasi gawat darurat RSUPNCM. Maj Obstet awareness among pregnant women for doing ante- Ginekol Indones 2009; 33(3): 135-42. natal care (ANC) or lack of screening facility in the 5. WHO. WHO recommendation for prevention and treatment of pre-eclampsia and eclampsia. WHO recommendation, primary health services. Preeclamptic patients who 2011. Cunningham F, Gant N, al e. Williams obstetrics. 24 came to the emergency unit on Dr. Cipto Mangun- ed. New York: McGraw-Hill; 2014. kusumo hospital were generally without complica- 6.Sibai B, Dekker G, Kupfermin M. Pre-eclampsia. Lancet tions. The complication of preeclampsia with severe (London, England) 2005; 365: 785-99. Vol 4, No 4 October 2016 HSP 70 level in threatened abortion 183

Research Article

Heat Shock Protein 70 (HSP 70) Level in Threatened Abortion Kadar Heat Shock Protein 70 (HSP 70) pada Abortus Iminens

Bram M Utomo, Eddy Suparman, Linda M Mamengko Department of Obstetrics and Gynecology Faculty of Medicine Universitas Sam Ratulangi/ Prof. dr. RD Kandou Hospital Manado

Abstract Abstrak

Objective: To determine the level of Heat Shock Protein 70 (HSP 70) Tujuan: Mengetahui perbandingan kadar Heat Shock Protein 70 (HSP in threatened abortion compared with normal pregnancy. 70) pada abortus iminens dibandingkan dengan kehamilan normal. Method: This was a cross-sectional analytic study design conducted Metode: Penelitian potong lintang analitik secara komparatif dila- to examine the HSP 70 level on 25 subjects of pregnant women with kukan dengan memeriksa kadar HSP 70 pada 25 wanita hamil de- <20 weeks of gestation and 30 subjects with threatened abortion. It ngan usia kehamilan kurang dari 20 minggu dan 30 subjek dengan was held at Obstetrics outpatient clinic Prof. dr. RD Kandou Manado abortus iminens. Penelitian ini dilakukan di unit rawat jalan Obstetri Hospital. The data obtained were analyzed using SPSS software RS Prof. dr. RD Kandou Manado. Kami melakukan analisis dengan version 22.0 and we did the discussion using the existing literature SPSS versi 22,0 dan diskusi menggunakan teori literatur yang ada. theory. Hasil: Dari analisis statistik dengan menggunakan Uji Mann-Whitney Result: The statistical analysis using the Mann-Whitney test showed menunjukkan terdapat perbedaan yang bermakna pada kadar HSP that there were significant differences of median level of HSP 70 70 antara kelompok aborsi iminens dengan kehamilan normal kurang between threatened abortion group and normal pregnancy with less dari 20 minggu (p<0,001). than 20 week of gestation (p<0.001). Conclusion: Heat Shock Protein 70 can be a marker to predict the Kesimpulan: Heat shock protein 70 dapat menjadi marker untuk risk of miscarriage in the first trimester of pregnancy. memprediksi risiko abortus pada trimester pertama kehamilan. [Indones J Obstet Gynecol 2016; 4-4: 183-186] [Maj Obstet Ginekol Indones 2016; 4-4: 183-186] Keywords: HSP 70, pregnancy, threatened abortion Kata kunci: abortus iminens, HSP 70, kehamilan normal

Correspondence: Bram M. Utomo, [email protected]

INTRODUCTION Cells undergoing environmental stress will encounter the heat shock response (HSR). This Pregnancy is one of frightening events for old cou- response mechanism will involve cell protection ple because many complications often occur on called as heat shock protein (HSP) to help an that age.1 Threatened abortion as one of complica- organism dealing with the environmental tions is a bleeding happening less than 20 weeks pressure.3 The role of other cellular processes to of gestation. It can continue for several days or re- oxidative stress is called as an ischemic condition. cur and it is usually accompanied by slight pain on Therefore, member of HSP 70 and co-chaperones the lower abdomen or back pain as like the men- play an essential role to sort and control the pro- strual period.1 Currently, around 15% of women tein quality through selecting and directing protein experience the spontaneous abortion at the con- to the proteasome. As known, the proteasome has ception; however, most of it occur without reali- function to disintegrate of damage protein and HSP zing of it. Meanwhile, 15-20% cases ended with assists its function. spontaneous abortion or ectopic pregnancy.2 More than 80% of abortion happen in the first trimester Heat shock protein is a conservative primary of gestation up to 14-week gestational age.1 Apart structure of polypeptide which depends on mo- from that, abortion can also be caused by the im- lecular weight. It can be divided into macromole- balance between oxidants and anti-oxidants in cule (HSP 100 and HSP 90), medium molecule (HSP uteroplacental; whereas, this balance has an im- 70, HSP 60, and HSP 40), and the low molecule portant role in various diseases including abortion. (HSP 27 and HSP 10).4 Many studies stated that Indones J 184 Utomo et al Obstet Gynecol HSP 70 influences in variety diseases, such as heart all pregnant women coming to Obstetrics outpa- disease, cancer, acute infection, asthma, and patho- tient clinic at Prof. dr. RD Kandou Manado Hospital logical pregnancy. Heat shock protein 70 also plays from February to April 2016. a role in embryogenesis and reproductive cycle. Ex- The inclusion criteria were women with threat- tracellular protein of HSP 70 is able to induce pro ened abortion and normal pregnancy with gesta- inflammatory immune response (Th1).2 Actually, tional age less than 20 weeks. The collection of the concentration level of HSP 70 decreases in nor- samples was calculated by using a single average mal pregnancy. The HSP 70 presents in the peri- formula. After calculating, the minimal samples pheral circulation of normal pregnancy. In the consisted of 16 threatened abortion women and 16 meantime, its concentration will decrease as the in- normal pregnancy with <20 weeks of gestation. We crease of gestational age. However, it has negative excluded all women with molar pregnancy, abnor- correlation to maternal age. Decreasing level of malities of the uterine, myoma uterine, gestational HSP 70 may lead to the immunological tolerance diabetes mellitus, and pregnancy-induced hyper- process to the fetus. Indeed, HSP 70 concentration tension. level is associated with an increased risk of some pregnancy complications.3 We examined the level of HSP 70 from subjects’ blood through ELISA in Manado Prokita laboratory. Intracellular expression of HSP 70 can lead to We did the analysis using Mann-Whitney test to other obstetrical complications, namely abortion. assess the mean level of HSP 70 on imminent The HSP 70 in syncytiotrophoblast between 8 and abortion group compared with normal pregnancy. 9 week-gestational age will increase sharply. Mean- The data obtained were processed using the soft- while, the increase of HSP 70 from placenta in the ware program of Statistical Product and Service first trimester indicates the miscarriage process. In Solution (SPSS) for Windows version 22.0. addition to that, the increase level of HSP 70 on lymphocytes is associated with high risk pregnancy as it signs early onset of pregnancy failure.4 Al- RESULTS though intracellular HSP 70 has anti-inflammatory effect, extracellular HSP 70 may act as stress signal During the study, we collected 55 subjects of preg- molecule from non-physiological condition, such as nant women. Table 1 showed the characteristics of cellular stress or damage, simultaneously with pro subjects in this study. Actually, only age and ges- inflammatory cytokines both innate or adaptive tational age had normal distribution between response. Extracellular HSP 70 binds to surface re- threatened abortion and normal pregnancy group ceptors (CD14, CD36, CD40, CD91, LOX-1, Toll-like (p>0.05) based on Kolgomorov-Smirnov test. receptor 2 and 4) on the Antigen Presenting Cell Meanwhile, the other characteristics did not (APC) and stimulates the proinflammatory cytoki- describe normal distribution between the groups. nes, such as tumor necrosis factor- (TNF-), in- Table 2 indicated the average level serum of HSP terleukin (IL-1 and IL-6), chemokines, and nitric 70 between the groups. In threatened abortion oxide production, as well as expression of mole- group, the mean, SD, median, and min-max were cules. The role of cytokines in the inflammatory 1.5, 0.3, 1.4, and 1.1-2.2 pg/ml; respectively. Mean- reaction in whole process is a response to elimi- while, we obtained serum level of HSP 70 in normal nate inflammation.5,6 pregnancy group with the mean (SD) of 0.3 (0.1) According to the theory, in the first trimester, pg/ml and median (min-max) of 0.3 (0.2-0.4) the placenta will filtrate the maternal blood; thus, pg/ml. the plasma level of HSP 70 will increase in miscar- Through using non-parametric statistical test of riage pregnancy compared with normal pregnancy. Mann-Whitney, we got the significant difference This study aims to determine the level of HSP 70 (p<0.001) of the median level of HSP 70 between in threatened abortion compared with normal threatened abortion and normal pregnancy groups. pregnancy. Therefore, the concentration of HSP 70 was asso- ciated with the occurrence of threatened abortion. METHODS DISCUSSION This was an analytic observational using cross sec- tional study design. We held the study by recruiting Table 1 described the 55 subjects recruited in this Vol 4, No 4 October 2016 HSP 70 level in threatened abortion 185

Table 1. The Characteristics of Subjects Theatened Abortion Normal Pregnancy Characteristics N(%)N(%) Age (years old)* 18-23 9 30 10 40 24-29 11 37 10 40 30-34 10 33 4 16 35-39 0014 History of miscarriage Never 19631872 1 times 5 17 5 20  2 times 6 20 2 8 Education Elementary 0000 Middle School 0014 High School 29 97 24 96 Undergraduate 1300 Smoking Yes 1300 No 29 97 25 100 Gestational age* 0-6 weeks 0000 6-12 weeks 18 60 12 48 12-20 weeks 12 40 13 52 *Normal distribution (p>0.05)

Table 2. The Level Serum of HSP 70 HSP 70 levels (pg/ml) Group N p Mean SD Median Min­max Threatened Abortion 30 1.5 0.3 1.4 1.1 - 2.2 < 0.001 Normal pregnancy 25 0.3 0.1 0.3 0.2 - 0.4

study. Women on 24-29 years old (37%) were the carriage. Study by Lena L, et al. in Poland, there largest age group for threatened abortion; while, was significant relationship between level of HSP both 18-23 and 24-29 years old (40%) were the 70 and history of recurrent miscarriage on largest group for normal pregnancy. This study threatened abortion group.9 Of educational level, showed there was not association between age and we found the incidence of threatened abortion and incidence of abortion. Based on study by Baqur AS, normal pregnancy was more common on high et al. in India, they explained that between 24 and school (97% and 96%). According to smoking 29 years old was the highest group for miscarriage history, we found that almost all subjects never had in 2013.7 Meanwhile, Tan Hao study in China smoking habit. Study by Hao Tan, et al. in 2007 stated the average group of women undergoing concluded there was significantly different miscarriage was 26 years old in 2007.8 From our between smoking habit and abortion in China.8 study, we got that 63% of threatened abortion Based on gestational age, we found that the group was never experienced miscarriage and 72% prevalent in 6-12 weeks of gestation (60%) and of normal pregnancy did not have history of mis- <20 weeks of gestation (52%) for normal preg- Indones J 186 Utomo et al Obstet Gynecol nancy group. According to the study by Xiangjun proinflammatory cytokines, including IL-1, IL-6 Gong, et al. in 2012, they found the most frequent and TNF-. These cytokines would further cause of abortion happened in 6-12-week-gestational age the abortion.13 because women felt anxiety and depression in the first trimester.10 Meanwhile, Adams, et al. through their study in 2007 stated that miscarriage in the CONCLUSION first trimester is usually caused by fetal factors; whereas, 20% of them are due to fetal abnor- Heat Shock Protein 70 can be a marker to predict malities.11 the risk of miscarriage in the first trimester of pregnancy. Table 2 indicated that the mean level of HSP 70 in threatened abortion group was 1.51 (SD 0.3) pg/ml with a median level of 1.4 (1.1-2.2) pg/ml. REFERENCES While, the level of HSP 70 in normal pregnancy group was 0.3 (SD 0.1) pg/ml with a median level 1. Cunningham FG, Leveno KJ, Bloom SL, et al. Williams Obs- tetrics. Twenty third edition. The McGraw-Hill Companies. of 0.3 (0.2-0.4) pg/ml. Based on study by Baqur AS, 2010: 50. et al. in India, the mean level of HSP 70 in 2. FU Hartl, MH Hartl. Molecular chaperones in the cytosol: threatened abortion group was from 1.06 to 1.54 From nascent chain to folded protein: Science 2002; 295: pg/ml.7 Our result was not too different from 1852-8. Molvarec, et al. in Hungary, they got the mean 3. Haslbeck M, Franzmann T, Weinfutner D, et al. Some like it level of HSP 70 in normal pregnancy was between hot: the structure and function of small heat-shock proteins: 0.27 and 0.39 pg/ml.12 Na. Struct Mol Biol, 2005; 12: 842. 4. Jauniaux E, Hempstock J, Greenworld N, et al. Trophoblastic. The non-parametric statistical test using Mann- Oxidative Stress in relation to Temporal and Regional Dif- Whitney showed the significant difference of HSP ferences in Maternal Placental Blood Flow in Early Normal and Abnormal Pregnancies. Am J Pathol, 2003; 162: 115-25. 70 medial level between threatened abortion and normal pregnancy group (p<0.001). It meant that 5.LH Pearl, C Prodromou. Structure and mechanism of the HSP90 molecular chaperone machinery: Annu. Rev Bio- the HSP 70 had association with abortion. Tan Hao chem. 2006; 75: 271. based study in China said that there was positive 6. Morimoto RI. Regulation of the heat shock transcriptional correlation between HSP 70 and miscarriage.8 In response: cross talk between a family of heat shock factors, contrary to the result, Lena N, et al. in Poland molecular chaperones, and negative regulators. Genes Dev, through their study concluded that there was no 1998; 12: 3788-96. significant relationship in HSP 70 on both 7.Baqur AS, Kafil A, Raad AA, et al. Heat Shock Protein (Hsp70) Aborted Levels In Women With Toxoplasma gondii miscarriage and normal pregnancy group. The Infection. Int J Applied Biol Pharma Technol, 2013; 4: ...-... reason was due to the limitation of smaller sample 8. Tan H, Xu Y, Xu J, et al. Association of Increased levels of and they took the sample at 6 weeks’ post abortion heat shock protein 70 in the lymphocyte with high risk of which might influence the result.9 adverse pregnancy outcomes in early pregnancy: a nested case-control study. Cell Stress chaperones, 2007; 12: 230-6. Increased level of HSP 70 in the blood circula- 9. Lena NL, Sypniewska GO, Michalkiewicz J, et al. Evaluation tion was considered not only as marker of patho- Of Serum Heat Shock Protein 70 Concentration In Women logical processes, but also having important role in With Recurrent Miscarriages. Folia Medica Copernicana, the pathogenesis of abortion. According to 2013; 1(2): 58-61. Jauniaux, et al. in 2003, they stated that the 10. Gong Xiangjun, Jiahu Hao, Fangbiao Tao, et al. 2012. Preg- nancy loss and anxiety and depression during subsequent increased expression of HSP 70 in the placenta at pregnancies: the data from the C-ABC study. Eur J Obstet the first trimester caused the miscarriage and it Gynecol Reprod Biol. 2012; 166: 30-6. had an essential role to the abortion process.4 11. Adams KM, Yan Z, Stevens AM, The changing maternal "self" Meanwhile, according to Hao Tan in 2007, the level hypothesis: a mechanism for maternal tolerance of the fe- of HSP 70 on lymphocytes found to be associated tus. Placenta, 2007; 28: 378-82. with the risk of pregnancy; however, it was not 12. Molvarec A, Rigo J Jr, Nagy B. Serum levels of heat shock protein 70 are Decreased in normal human pregnancy. J good as the marker for the first trimester of preg- Reprod Immunol, 2007; 74: 163-9. nancy.8 Meanwhile, Koga, et al. in 2010 through 13. Koga K and Mor G. Toll-like receptors at the Maternal-Fetal their study said that HSP 70 could occupy the Interface in normal pregnancy and pregnancy disorders. extracellular toll-like receptor (TLR) inducing Am J Reprod Immunol, 2010; 63(6): 587-600. Vol 4, No 4 October 2016 Effect of rectal misoprostol to blood loss 187

Research Article

Effect of Rectal Misoprostol to Blood Loss at High Risk Pregnancy Efek Pemberian Misoprostol Per­rektal terhadap Jumlah Perdarahan pada Kehamilan Risiko Tinggi

Daniel Liando, IMS Murah Manoe, Eddy R Moeljono Department of Obstetrics and Gynecology Faculty of Medicine Universitas Hasanuddin/ Makassar

Abstract Abstrak

Objective: To compare the effectiveness of rectal misoprostol ad- Tujuan: Untuk membandingkan jumlah perdarahan kala IV persalin- ministration to the amount of blood loss in 4th stage of labor at high an yang diberikan misoprostol per rektal segera setelah lahirnya risk pregnancy. plasenta pada kehamilan risiko tinggi. Method: We recruited all pregnant women with high risk criteria in- Metode: Seluruh ibu hamil dengan salah satu kriteria risiko tinggi yang ditetapkan yaitu anemia, usia  35 tahun, atau kehamilan  4. cluding anemia, age  35 years old, or the number of pregnancies Ibu yang akan bersalin tersebut dilahirkan sesuai prosedur Asuhan  4. Women would deliver appropriate to standard procedure of Persalinan Normal. Pada kelompok perlakuan, setelah lahirnya pla- normal delivery. After that, we gave 400-mcg tablet of misoprostol senta, pasien segera diberikan tablet misoprostol 400 mcg per rektal. rectally in treatment group. To count the amount of blood loss Tetapi pada kelompok kontrol, tidak diberikan tablet misoprostol. Ke- during 4th stage of labor, we put the underpad. mudian diletakkan alas bokong untuk menampung darah yang keluar selama kala IV persalinan. Result: The amount of blood loss in 4th stage of labor in the treat- ment group was 201.1 (SD 80.3) ml less than the control group Hasil: Jumlah perdarahan pada kala IV persalinan kelompok per- (285.9 (SD 93.2) ml). The result showed that the administration of lakuan yaitu sebanyak 201,1 (SD 80,3) ml, lebih sedikit dibanding de- 400-mcg misoprostol tablet rectally immediately after the birth of ngan kelompok kontrol yaitu sebanyak 285,9 (93,2) ml. Dari hasil uji analisis didapatkan bahwa pemberian tablet misoprostol 400 mcg per the placenta at high risk pregnancy impacted significantly to reduce rektal segera setelah lahirnya plasenta pada kehamilan risiko tinggi the amount of blood loss in 4th stage of labor (p<0.001). The inci- mempunyai pengaruh yang signifikan untuk menurunkan jumlah per- dence of post-partum haemorrhage in the treatment group was darahan kala IV persalinan (p<0,001). Jumlah perdarahan kala IV 3.3% and 10% in control group. The drug side effects complained 500 ml pada kelompok perlakuan yaitu sebanyak 3,3% lebih sedikit were nausea (6.7%) and shivering (3.3%). dibandingkan dengan kelompok kontrol yaitu sebanyak 10%. Dite- mukan efek samping obat pada sebagian kecil sampel berupa mual Conclusion: Administration of 400 mcg rectal misoprostol after de- (6,7%) dan menggigil (3,3%). livering the placenta in high risk pregnancy has significant influence to reduse the amount of blood less in fourth stage of labor. Kesimpulan: Pemberian 400 mcg misoprostol per rektal setelah pengeluaran plasenta pada kehamilan risiko tinggi dapat menurun- [Indones J Obstet Gynecol 2016; 4-4: 187-189] kan jumlah perdarahan pada kala IV persalinan. Keywords: 4th stage of labor, misoprostol, rectal, the amount of [Maj Obstet Ginekol Indones 2016; 4-4: 187-189] blood loss Kata kunci: jumlah perdarahan, kala IV, misoprostol, rektal

Correspondence: Daniel Liando; [email protected]

INTRODUCTION grafi Kesehatan Indonesia (SDKI) in 2012, the mortality rate in Indonesia was around 359 per Postpartum haemorrhage (PPH) is a bleeding oc- 100,000 live births. This rate was increased from cured more than or equal with 500 cc after third 228 per 100,000 live births in 2007.2 stage of labor.1 Postpartum haemorrhage is one of major pregnancy complication which is happened Uterine atony is the commonest cause of PPH around 4-6% of vaginal delivery and it becomes contributing around 70% of PPH cases. It can be the main cause of maternal mortality and morbi- occurred right after delivery on both spontaneous dity. Each year, it causes 25-43% of maternal mor- or operative vaginal delivery and abdominal tality during delivery and it is related to 515,000- delivery.3 Moreover, uterine atony often becomes 600,000 cases of pregnancy death worldwide.1 the fastest killer for women in less than one hour According to survey conducted by Survey Demo- due to PPH. More than 90% cases of uterine atony Indones J 188 Liando et al Obstet Gynecol usually happen during the first 24 hours of Table 1 showed that blood loss volume in fourth delivery. Therefore, supervision and prevention of stage of labor fulfilling the high risk criteria. In PPH are the main concern.4,5 In general, 88% of study group, the mean of blood loss was around PPH takes place during four hours after delivery 201.1 (SD 80.3) ml and 285.9 (SD 93.2) ml in and anemia is the risk factor for massive PPH control group. Statistical analysis through among pregnant women in developing countries.6 independent t test showed that there was a significant difference in blood loss volume during Clinicians often use some types of prostaglandin fourth stage of labor in high risk pregnancy women in fourth stage of labor to prevent PPH; however, (p<0.001). active management of third stage had been pro- perly done. The most often prostaglandin agent used to prevent PPH is misoprostol.7 Table 1. The Effectivity of Rectal Misoprostol in High Risk Misoprostol as E1 prostaglandin is stable in high Pregnant Women Group temperature and it can be used orally, sublingually, Blood Loss (ml) Group Discrepancy p* or even rectally. Misoprostol has been massively in Mean Mean SD used in obstetrics and gynecology cases to induce Study group 201.1 80.3 the labor, management of abortion and PPH.8 84.8 <0.001 Bamigboye, et al. reported that 400-mcg miso- Control group 285.9 93.2 prostol given rectally is effective to prevent the * Independent T-Test PPH.9 This study aims to determine the effect of 400- Table 2. The Incidence of Postpartum Haemorrhage mcg rectal misoprostol given after delivering the The Amount of Blood Loss Study Group Control Group placental to the amount of bleeding in fourth stage in Stage 4 Labor N (%) N (%) of labor for high risk pregnancy.  500 ml 1 (3.3%) 3 (10%) < 500 ml 29 (96.7%) 27 (90%) METHODS Table 2 showed that there was only 3 of 30 This study was a randomized controlled trial held subjects in control group and 1 of 30 subjects in in delivery room of Dr. Wahidin Sudirohusodo study group experiencing more than 500 ml blood Hospital, Fatimah Mother and Child Hospital, loss in fourth stage of labor. Table 3 depicted the Pertiwi Mother and Child Hospital, Labuang Baji several side effects from rectal misoprostol Hospital in Makassar from November 2014 to including nausea (6.7%) and shivering (3.3%). February 2015. The sample were taken through consecutive random sampling. The number of samples of each group were 30 subject. We Table 3. Side Effects from the Study recruited the high risk pregnant women and showed anemia through laboratory test (hemo- Side Effect Study Group Control Group N (%) N (%) globin level  9 g/dl), age  35 years old, or grandemultipara ( 4 pregnancies). None 27 (90%) 30 (100%) Nausea 2 (6.7%) 0 (0%) Subjects in study group would immediately be given the 400-mcg rectal misoprostol right after Shivering 1 (3.3%) 0 (0%) delivering the placenta. Meanwhile, the control group did not get anything. After that, we put the underpad on the subjects’ bottom to measure the DISCUSSION amount of blood loss during fourth stage of labor. Data taken from this study were written down and This study showed that the amount of blood loss further analyzed using SPSS. in fourth stage of labor for the whole subjects was 285.9 (SD 93.2) ml in control group and 201.1 (SD RESULTS 80.3) ml in study group. The difference was occurred due to the rectal misoprostol mechanism There were 60 subjects taken consisted of 30 of action in study group to reduce the amount of subjects in each group of control and study. blood loss. The statistical analysis through in- Vol 4, No 4 October 2016 Effect of rectal misoprostol to blood loss 189 dependent t test showed there was CONCLUSION significantly different between study and control group of blood loss (p<0.001). A study by Laili The use of 400-mcg rectal misoprostol right after delivering the placenta in high risk pregnancy has Chilmawati in Yogyakarta described that the significant influence to reduce the amount of blood amount of blood loss in fourth stage of labor loss in fourth stage of labor. Parity as a risk factor among women who delivered vaginally was 102.13 is considered the strongest factors contributing the (SD 67.34) ml in control group. This distinction amount of blood loss. The management of PPH was happened due to the sample criteria of high with rectal misoprostol after delivering placenta as risk pregnant women. It made higher incidence of a prophylactic is recommended for high risk blood loss compared with the study done in pregnancy. In future, other studies should be 10 Yogyakarta. conducted to assess the impact of other high risk The result of this study showed the significant factors toward blood loss volume in fourth stage correlation between parity and the amount of of labor. blood loss in fourth stage of labor among both study (p=0.041) and control group (p=0.002). This REFFERENCES result revealed that blood loss in fourth stage of labor was mostly influenced by parity as one of risk 1. Cunningham F, Gart FN, Leveno J. The McGraw-Hill Compa- nies: Williams Obstetrics, 2001: 685-735. factors instead of other risk factors. The result of 2. BPS. Survei Demografi dan Kesehatan Indonesia. 2012: 1- this study was in accordance with the other study; 29. whereas, the parity is claimed as the highest risk 3. Cameron M and Robson S. Vital Statistic: An Overview. A of PPH among all others.11 Textbook of Postpartum Haemorrhage. 2006: 17-31. 4. JNPK-KR. Asuhan Persalinan Normal. Asuhan Esensial Per- The number of subjects with blood loss volume salinan. 2008: 123-44. more than 500 ml in fourth stage of labor were 3 5. Humera A. One Year Prospective Randomised Comparative (10%) and 1 (3.3%) in control and study group; Study Oral Misoprostol with Intravenous Methylergome- respectively. This result showed that 400-mcg trine in Prevention of Postpartum Haemorrhage in Cases High Risk for Postpartum Haemorrhage. Department of rectal misoprostol after delivering placenta could Obstetrics and Gynecology. 2001: 31-7. reduce the incidence of PPH in high risk pregnancy. 6. Versaevel N, Darling L. Prevention and Management of Misoprostol is the recommendation agent to Postpartum Hemorrhage. AOM Board of Directors. 2006: prevent PPH which has officially been published by 1-12. International Confederation of Midwives (ICM) and 7.WHO. WHO Recommendations for The Prevention of Post Partum Haemorrhage. 2007: 4-21. the International Federation of Gynecology and 8 8. Depkes-RI. Penggunaan Misoprostol di bidang Obstetri dan Obstetrics (FIGO). On the other hand, this study Ginekologi. 2008: 1-75. also found several side effects of rectal misoprostol 9. Carpenter JP. Misoprostol for Prevention of Postpartum including nausea (6.7%) and shivering (3.3%). In Hemorrhage: An Evidence-based Review by The United conclusion, the use of 400-mcg rectal misoprostol States Pharmacopeia. 2001: 1-6. is safe for the patients. 10. Chilmawati L, Pradjatmo H, Siswosudarmo HR. Pengaruh Pemberian Asam Traneksamat Terhadap Jumlah Perdara- han Pascasalin Pada Kelahiran Vaginal. J Kes Reprod. 2014: 15-32. 11. Willacy H. Postpartum Haemorrhage. Egton Medical Infor- mation System. 2015: 1-6. Indones J 190 Affandi et al Obstet Gynecol

Research Article

A Randomized Five­Year Comparative Study of Two Levonorgestrel­ Releasing Implant Systems: Norplant® Capsules and Jadena® Rods Penelitian Komparatif Acak Lima Tahun antara Dua Implan Levonogestrel: Kapsul Norplant© dan Batang Jadena©

Biran Affandi,1 Rusdi S Ridwan,2 R Hasan M Hoesni,3 Thamrin Tandjung,4 TM Ichsan,4 Rizani Amran,5 Heriyadi Manan,5 Eka R Gunardi,1 Noor Pramana,6 Suryo Hadiyono,6 Widohariadi,7 Suhartono DS,7 Retno B Farid,8 Mardiah Taher8 1Department of Obstetrics and Gynecology, Faculty of Medicine Universitas Indonesia, Jakarta 2National Coordinating Body for Family Planning, Jakarta 3Senior Trial Consultant, Private Consultant, Jakarta 4Department of Obstetrics and Gynecology, Faculty of Medicine Universitas Sumatera Utara, Medan 5Department of Obstetrics and Gynecology, Faculty of Medicine Universitas Sriwijaya, Palembang 6Department of Obstetrics and Gynecology, Faculty of Medicine Universitas Diponegoro, Semarang 7Department of Obstetrics and Gynecology, Faculty of Medicine Universitas Airlangga, Surabaya 8Department of Obstetrics and Gynecology, Faculty of Medicine Universitas Hasanuddin, Makassar

Abstract Abstrak

Objective: To provide a randomized comparison between Jadena® Tujuan: Untuk mengetahui efikasi dan akseptabilitas antara Jadena© and Norplant® in terms of efficacy and acceptability among Indone- dan Norplant© di antara perempuan Indonesia. sian women. Metode: Penelitian ini merupakan fase 4, terbuka, acak, dan multi- Method: This study was a phase IV, open label, randomized, mul- senter di Indonesia. Subjek penelitian merupakan perempuan dewasa ticenter study throughout Indonesia. Subjects were Indonesian adult Indonesia yang teracak untuk menerima Jadena© atau Norplant© women who were randomized to receive Jadena® or Norplant® as sebagai metode kontrasepsi. Penelitian ini diambil dari 6 kota besar di their contraceptive method. The subjects were recruited from 6 Indonesia yaitu Medan, Palembang, Jakarta, Semarang, Surabaya, dan large cities in Indonesia, such as Medan, Palembang, Jakarta, Sema- Makassar. rang, Surabaya, and Makassar. Hasil: Dari total 600 subjek, 301 menggunakan Jadena© dan 299 Result: Of 600 subjects, 301 women getting to Jadena® and 299 mengunakan Norplant© pada periode Agustus 1998 hingga Februari women to Norplant® were enrolled between August 1998 and 1999. Rerata usia ialah 29,8 (SD 5,3) tahun berkisar antara 18 hingga February 1999. The mean age was 29.8 (SD 5.3) years old, ranging 40 tahun. Tidak ada kehamilan yang terjadi selama periode observasi. from 18 to 40 years old. We did not find the pregnancy during the Kemungkinan hamil setelah 1 tahun antara Jadena© (0,920 (SD study. Non-pregnancy probability at the end of one year was similar 0,016)) dan Norplant© (0,916 (SD 0,084)). Angka kebertahanan between Jadena® (0.920 (SD 0.016)) and Norplant® users (0.916 penggunaan Jadena© pada tahun 1 dan tahun 3 ialah 95,3% dan (SD 0.084)). The continuation rates of Jadena® at one and three-year 66,8%, sementara pada Norplant© ialah 94,3% dan 70,2%. were 95.3% and 66.8%; whereas, the continuation rates of Norplant® was 94.3% at year-1 and 70.2% at year-3. Kesimpulan: Sistem subdermal levonogestrel 2 batang (Jadena©) memiliki efikasi yang mirip dengan sistem subdermal lama Conclusion: The new two rod levonorgestrel subdermal system © (Jadena®) showed similar efficacy with the old six capsule menggunakan 6 kapsul (Norplant ) dalam mengontrol kehamilan. levonorgestrel subdermal system (Norplant®) in term of birth Kedua sistem implan memiliki profil tolerabilitas yang serupa. Jadena© lebih mudah dimasukkan dan dikeluarkan daripada control. Both implant systems also have similar tolerability profile. © Jadena® is easier to insert and remove than Norplant®. Norplant . [Indones J Obstet Gynecol 2016; 4-4: 190-197] [Maj Obstet Ginekol Indones 2016; 4-4: 190-197] Keywords: birth control, efficacy, implant Kata kunci: efikasi,implan, kontrol kehamilan

Correspondence: Biran Affandi, [email protected]

INTRODUCTION administered alone is progestin only contraceptive Levonorgestrel (LNG) is a synthetic progestin used pills (known as mini pills), Norplant® and Jadena® for contraception either alone or in combination subdermal implant, and the intrauterine LNG with ethynyl estradiol. The preparation in LNG system (Levonova® or Mirena®). Vol 4, No 4 October 2016 A randomized five year comparative study 191 Levonorgestrel primarily acts through thicken- terms of efficacy and acceptability among Indone- ing the cervical mucus; thus, it will obstruct the sian women. sperm penetration into the uterus.1,2 Besides, it also inhibits ovulation in over 50% of the mens- trual cycles3,4 and has a suppressive effect on the METHODS endometrium to reduce the likelihood of nidation.5 This study was a phase IV, open label, randomized, Both mechanism of action above provide protec- and multicenter studies throughout Indonesia. tion against pregnancy efficiently. Subjects were recruited from 6 large cities in Indo- The beneficial features of Norplant® include nesia, namely Medan (Universitas Sumatera Utara), long contraceptive activity, high contraceptive effi- Palembang (Universitas Sriwijaya), Jakarta (Uni- cacy, absence of estrogen side effects, and conve- versitas Indonesia), Semarang (Universitas Dipo- nience due to no daily attention needed. Further- negoro), Surabaya (Universitas Airlangga) and more, it is completely reversible and the side- Makassar (Universitas Hasanuddin) between effects are mainly mild and transient. Norplant® August 1998 and February 1999. capsules have been studied extensively for clinical Subjects were Indonesian adult women having efficacy and safety by independent clinicians and been randomized to receive Jadena® or Norplant® agencies throughout the world for many years. as their contraceptive method. The sample size was However, insertion and removal of the implant determined through formula proposed by Pocock. needs sufficient training. To demonstrate a ten-fold increase in cumulative On the other hand, Jadena® is developed as two 3-year pregnancy rate (0.5 per 100 women-years), implantable rods in order to make insertion and the minimum sample size was 272 subjects per removal of the contraceptive device easier. Both treatment group. the release rate of LNG from Jadena® rods and A total of 600 women were needed which meant plasma hormone concentrations achieved are com- 100 women recruited from each center. This study parable to those of the Norplant® capsules.6,7 The was the first design to be followed-up for three two preparations are similar in terms of contracep- years; however, another 2 years were added to tive efficacy for three years and the occurrence of complete 5-year observation and follow-up. Sub- side effects.8-10 jects were followed every year in 12 visits, such as Jadena® is a subdermal tube implant containing at month-1, 3, 6, 12, 18, 24, 30, 36, 42, 48, 54, and 75 mg of LNG each, whereas Norplant® is a sub- 60. We recruited 18-40-year old women, not cur- dermal capsule containing 36 mg LNG each. rently pregnant, be regularly exposed to the risk of Jadena® implant consists of two rods sizing nine pregnancy, without exposure to injectable steroid millimeters longer than the Norplant® capsules. in the predicting 6 months, be willing to rely solely The period of Jadena® rod user is for three years; on the implant randomly assigned for her contra- meanwhile, the Norplant® capsules provide longer ceptive method, be willing to return the clinic for period for five years of effective contraceptive regular follow-up. All the participants were in- protection. formed of the purpose, risk, and benefits of the

® study and they had to sign the written informed Norplant was introduced into the Family consent. Planning Program (FPP) in Indonesia since 1981. It becomes popular among Indonesian commu- Subjects were excluded from the study if there nity.9 By March 1997, there were 2.4 million was any kind of cancers, undiagnosed abnormal women using Norplant® as their contraceptive uterine bleeding (AUB); thromboembolism or se- method in Indonesia. This represents about three vere cardiovascular problem; mental illness, de- quarters of Norplant® users all over the world. pression or epilepsy; severe and frequent head- Recently, Jadena® was also registered in Indonesia aches; diabetes mellitus; active liver disease or and it had already been used by about 2,000 Indo- jaundice; regular treatment with enzyme-inducing nesian women. However, data comparing the drugs, such as barbiturates, phenytoin, carbama- efficacy and acceptability of Norplant® and zepine or rifampicin; blood pressure greater than Jadena® are still not available in Indonesia. There- 160 mmHg systolic or 100 mmHg diastolic; bloody fore, this study aims to provide a randomized breast discharge; severe hirsutism; pregnancy or comparison between Jadena® and Norplant® in suspected pregnancy; current evidence of pelvic Indones J 192 Affandi et al Obstet Gynecol inflammatory disease; and participation in another point four percent of these women had amenor- clinical study on the previous three months. rhea. Almost one-third (32.5%) of the subjects wanted more children. The most popular (49.8%) contraceptive method used prior to the study en- Study Endpoints rollment was the combination of oral contraceptive The primary efficacy variable was the pregnancy and majority of them (38.7%) had their last con- rate calculated using the Kaplan-Meier product traceptive used less than 31 days before. More than limit method. Secondary efficacy parameters were half of the women (60.3%) did not practice breast- the alteration in menstrual cycles, discontinuation feeding. Almost all subjects (95%) reported vaginal or continuation rates, rates of implant removal due delivery at the last pregnancy. Cytological exami- to menstrual problems and/or medical reasons, nation data were available in 591 subjects. The re- and the duration of implant insertion and removal sults were mostly classified into CI (75.1%), while from asepsis to wound closure. All data were based CII was found in 24.2% of women. None was clas- on the information reported by the women using sified as CIII. Jadena® or Norplant®. We also investigated several safety parameters including laboratory parame- Efficacy Assessment ters, general state of health, adverse events, con- comitant medications, body weight, and vital signs. Primary end point Data Management and Analyses No pregnancy was observed in both contraceptive users. However, an intrauterine pregnancy was All variables were described according to their found in Norplant® group which had been con- types using univariate statistics (mean and stand- firmed that it started before her enrollment into ard deviation for continuous data, frequency and the study. The implant was removed immediately percentage for categorical data). The primary effi- and she delivered a baby spontaneously at term cacy variable in this trial was the pregnancy rate gestational age. The Kaplan-Meier product limit estimated using the Kaplan-Meir product limit method showed that non-pregnancy probabilities method. The two treatment groups were compared were not different between the two implants (Ta- using the Wilcoxon rank-sum test. A significance ble 2). Therefore, both contraceptive methods level (-level) of 0.05 was used for all statistical showed similar efficacy in controlling pregnancy tests. Secondary and safety variables were pre- over 5 years. sented descriptively.

RESULTS Secondary endpoints There were 600 women enrolled in this study. The prevalence of dysmenorrhea was considered They were randomized to receive Jadena® (301 low. The prevalence was not significantly different women) or Norplant® (299 women). Their mean between baseline and after 5 years both in women ® age was 29.8 (SD 5.3) years old, ranging from 18 using Jadena (2.0% vs. 2.5%; p=0.812) and Nor- ® to 40 years old. Subjects using Norplant® were plant (2.4% vs. 2.0%; p=0.977). The menstrual older than subjects using Jadena® (p=0.008). On changes occurred in majority of subjects in the first the average; however, the women from both im- two years. Improvement of menstrual irregulari- plant groups were relatively similar to the demo- ties increased after three years. The pattern of ® graphic characteristics, such as body weight, body menstrual changes was similar between Jadena ® mass index (BMI), and blood pressure (Table 1). and Norplant users (Figure 1). All subjects had normal body weight and BMI. All subjects had been pregnant and/or had delivered Discontinuation or continuation rates at least once. The mean number of previous preg- nancies were 2.8 (SD 1.5). The mean number of At the end of the third year and after obtaining live birth were 2.6 (SD 1.4). Higher parity was ob- written consent to extend the observation period served in women on Jadena® than Norplant® by an additional 2-year, 411 of the 600 women (p=0.04). At baseline, most women (87.6%) re- (68.5%) agreed to continue the study; consisting ported normal or usual menstrual pattern. Five- of 210 women using Norplant® (70.2%) and 201 Vol 4, No 4 October 2016 A randomized five year comparative study 193 women using Jadena® (66.8%). Continuation rates (DHF) and it was not related to the contraceptive per year were shown on Table 3. The difference in method. discontinuation rates between the two contracep- Adverse events reported by women using tive methods from year-1 to year-5 was not signifi- Jadena® included spotting (5 women), bleeding (3 cantly different (p=0.746). women), influenza (2 women), dizziness (2 wo- men), expulsion (1 woman), cardiomegaly (1 wo- Rates of implant removal due to menstrual pro- man), cramp at the implant site (1 woman), death blems and/or medical reasons due to DHF (1 woman), headache (1 woman), local infection (1 woman), menometrorrhagia (1 wo- Premature removal of the implant was decided by man), metrorhagia (1 woman), and numbness (1 154 out of 217 women. The reason mostly was woman). In women using Norplant®, the adverse because of the desire to get pregnant (19.4%). events were headache (5 women), spotting (3 Others had menstrual problems, such as metro- women), hypertension (2 women), influenza (2 rrhagia (4.1%), amenorrhea (3.2%), spotting women), local infection (2 women), abscess (1 (2.3%), prolonged menstrual flow (1.8%), and woman), bleeding (1 woman), dizziness (1 wo- heavy menstrual flow (1.4%). The details on the man), emesis gravidarum (1 woman), irregular primary reasons for implant removal in both bleeding (1 woman), numbness (1 woman), palpi- groups were given on Table 4. tation (1 woman), pelvic pain/dyspareunia (1 wo- man), and sweating (1 woman). Duration of the implant placement and removal Nearly all subjects (99.2%) had their implant DISCUSSION placed on their left upper arm. There were neither In the beginning, this study was designed for 3 reported complications nor difficulties encoun- years, but it was extended for another 2-year to tered during implant placement. From aseptic to complete a 5-year observation of both implant sys- skin closure, the surgical procedure took an aver- tem. The first study on extended use (5 years) of age of 3.1 (SD 1.5) minutes, varied from as short the two-rod implants (Norplant II®) was conducted as 1 minute to as long as 10 minutes. The proce- in China, with a failure rate of 0.65 per 100 users ® dure for Jadena placement was shorter than Nor- and continuation rate of 65.3 per 100 users. These ® plantS (2.2 (SD 0.9) vs. 4.1 (SD 1.3) minutes; rates were similar to that of the capsule implant p<0.001). users.8 Continuation of two-rod LNG implants has The surgical procedure for implant removal took also been tried in US study when the 3-year cumu- an average of 8.7 (SD 4.9) minutes. Procedures for lative pregnancy rate was 0.8 per 100.10 For a 5- Jadena® removal was significantly shorter than year period, the 2-rod LNG implants were equiva- Norplant® removal (6.4 (SD 4.1) vs. 10.5 (SD 4.7) lent to the 6-capsule LNG implants regarding to minutes; p<0.001). Most subjects (89.5%) did not safety and efficacy parameters. It offers the advan- feel any complication during the procedure. tage to insert more easily and remove more ra- pidly.10 The cumulative 5-year pregnancy rate of LNG implants was comparable to that of tubal li- Safety Assessment gation.11 During the 5-year period, 37 (6.2%) of subjects Our study subjects were older (29.8 years old) experienced at least one adverse event (AE), com- than the US study, which had the mean age at base- prising 20 (6.6%) women on Jadena® and 17 line of 25.5 years old.10 This could be because all (5.9%) women on Norplant®. Most AEs (64.9%) subjects in our study was married women who had was mild; however, 6 women (16.2%) experienced given delivering at least once. It also reflects that moderate AEs, which all belonged to Jadena® contraceptive use is uncommon in young, unmar- group. Two patients had severe AEs; one on Nor- ried women adults in Indonesia. Other charac- plant® was diagnosed with severe hypertension teristics in this study were the subjects’ body during visit-11 and the another one on Jadena® ex- weight and BMI, which showed the normal range. perienced severe cramping on the arm at visit-11 On the contrary, subjects in the US study showed which requested to be removed. One woman on much higher body weight with a mean of 62.4 kg Jadena® died due to dengue hemorrhagic fever at baseline.10 Weight gain is an important problem Indones J 194 Affandi et al Obstet Gynecol during implant use; thus, it should be considered the prevalence increased to almost 70% at the end since the beginning. of five years. Amenorrhea was uncommon after two years of use.18 The primary reason for discontinuation after three years of use was the subjects’ plan for preg- Removal due to headache (4.7%) and weight nancy. However, a substantial number of subjects gain (4.0%) were the next most frequent medical (more than 70%) also experienced menstrual pro- reasons after menstrual problem in US study.10 In blems. Menstrual irregularities (lighter or heavier our study, only three subjects asked the implants menstrual flow and amenorrhea) were occurred in remove for headache and one subject for having most subjects at the first year of use. Although weight gain. Increased body weight of 1 kg per year menstrual change was common, most subjects de- on average was observed in implant users.11 cided to continue the implants. The overall level of Higher body weight gain of 2.9 kg was observed in satisfaction was high and even the continuation intrauterine LNG device at 12 months.19 rates at the end of the first year were better than Other rare adverse effects that might be a medi- 12 combined oral contraception. Menstrual change cal concern were local infection and hypertension. was also reported as the common AE during the Local infection was rare (0.4 per 100 users at 24 ® first year of Norplant use in Singapore. However, months) in the phase III clinical trial of 2-rod im- these menstrual irregularities appeared to be re- plant.17 A study among 2,674 Norplant® acceptors duced as the time and they were tolerated since from 7 countries and followed for one year showed 97% of the women continued at the end of the first that the incidence rate of infection was low (0.8%). 13 year. Study on bleeding patterns on 234 Nor- Insertion site infection and implant expulsion were ® plant users for 5 years showed that a substantial reported after the first two months of use.20 A number of subjects (66.3%) had irregular cycles study on 267 Norplant® users showed that neither during the first year and 7.1% were amenorrhea. systolic nor diastolic blood pressures were af- However, by the fifth year of use, only 37.5% sub- fected. Increasing blood pressure was more likely jects had irregular cycles and none had amenor- to be associated with the women’s age, obesity and rhea. Thus, the menstrual irregularity improved af- family history of hypertension.21 ter the first year of use.14 In this study, Jadena® use was associated with In a minority of subjects, prolonged bleed- significant shorter time of insertion and removal. ing/spotting (8.2%) and irregular bleeding (5.6%) In a 3-year randomized, controlled study, implant were the primary reasons for removal.10 A study removal of the 2-rod system took about half the among Norplant® users in Europe found that dis- time required for 6-capsule implants (p<0.001).22 continuation before 5 years of implant was related Difficult implants removal might be occurred in mostly to irregular bleeding.15 Risk factors for Nor- about 3% subjects due to deeply placed or poorly plant® discontinuation for perceived menstrual aligned implant or severe reaction to local anes- problems were higher education level (more than thetic agent.11 Implant removal was more difficult 12 years), had used no contraceptive in the pre- than insertion because in step of time, fat and fi- ceding month before Norplant® insertion, or had a brous tissue could develop around the capsules. relatively long duration of menstrual flow at ad- Delayed removal of implant could be seen in many mission.16 Discontinuation rate due to menstrual Norplant® users in Indonesia. A large study invol- problems increased from 9.4 per 100 women at the ving 2,979 Indonesian women using Norplant® in end of year-2 to 16.4 per 100 women at the end 14 provinces showed that 66% of the women had of year-5.16 implant removal by the end of the fifth year (90% by sixth year).23 Therefore, the 2-rod implant sys- In a phase III clinical trial, the 2-rod subdermal tem which was easier to insert could potentially implants showed high continuation rates, such as reduce the difficulties during implant removal after 88.1% at 1 year of use and 73.5% after 2 years. a long period of use. The main reason for discontinuation was men- strual disturbance, mainly prolonged bleeding.17 Cervical cytology might be a concern among Menstrual irregularity with the 2-rod system was women who used long-term hormonal contracep- not significantly different from that observed with tion. However, subdermal LNG implant has been Norplant®. Normal menstrual bleeding was un- proved to be safe during five years of use.24 In this common during the first three months of use, but study, there was no abnormal cytology or cervical Vol 4, No 4 October 2016 A randomized five year comparative study 195

Table 1. The Characteristics of the Study Subjects (n=600) Jadena® (n=301) Norplant® (n=299) Age, years (mean (SD)) 28.8 (1.3) 30.0 (1.7) Body weight, kg (mean (SD)) 50.7 (2.3) 50.9 (2.1) Body mass index, kg/m2 (mean (SD)) 21.9 (0.6) 22.1 (0.6) Systolic blood pressure, mmHg (mean (SD)) 112.9 (0.9) 113.4 (2.0) Diastolic blood pressure, mmHg (mean (SD)) 73.8 (1.9) 73.6 (2.3) Number of previous pregnancies (mean (SD)) 2.7 (0.4) 2.9 (0.4) Parity (mean (SD)) 2.5 (0.4) 2.7 (0.3) SD=standard deviation

Table 2. Kaplan-Meier Estimates for non-Pregnancy Probabilities* Jadena® (n=301) Norplant® (n=299) Probability SD Probability SD Year 1 0.920 0.016 0.916 0.084 Year 2 0.890 0.018 0.886 0.018 Year 3 0.664 0.027 0.702 0.026 Year 4 0.651 0.027 0.692 0.027 Year 5 0.000 0.000 0.000 0.000 Median time 60 months 60 months *Not significant at alpha 0.05; SD=standard deviation

Table 3. Continuation Rates of using Levonorgestrel Contraceptive Implant Year 1Year 2Year 3Year 4Year 5 n%n%n%n%n% Jadena® (n=301) 287 95.3 274 91.1 201 66.8 199 66.1 185 61.5 Norplant® (n=299) 282 94.3 273 91.3 210 70.2 208 69.6 198 66.2

Table 4. Primary Reasons for Discontinuation (Implant Removal) after Three Years* Primary reason Jadena® Norplant® Total No reason indicated 253257 Intrauterine pregnancy 0 1 1 Menstrual problems Frequent irregular bleeding 4 4 8 Heavy menstrual flow 2 1 3 Prolonged menstrual flow 1 2 3 Amenorrhea 3 4 7 Spotting 4 1 5 Placement problems Infection at site 1 4 5 Expulsion of 1 or more implants 1 2 3 Indones J 196 Affandi et al Obstet Gynecol

Primary reason Jadena® Norplant® Total Cardiovascular Hypertension 011 Not specified 2 0 2 Other medical problems Headache 1 2 3 Pain at the implant site 1 0 1 Weight change 1 0 1 Personal Planning of pregnancy 24 12 36 Widowed/divorced/separated 2 1 3 Moving 6 6 12 Other personal reasons Subject objection369 Husband objection123 Death of the husband 1 0 1 Not specified 10 5 15 Other removal problems 0 1 1 *multiple response

change to lead to premature removal or discon- 5. Shaaban MM, Ghaneimah SA, Segal S, Khalifa E-AM, Salem tinuation of both implant systems. HT, Ahmed A-G. Sonographic assessment of ovarian and en- dometrial changes during long-term Norplant use and their correlation with hormone levels. Fertil Steril. 1993; 59: 998- 1002. CONCLUSION 6. Robertson DN, Sivin I, Nash H, Braun I, Dinh J. Release rates of levonorgestrel from Silastic capsules, hemogeneous rods The new 2-rod LNG subdermal system (Jadena®) and covered rods in humans. Contracept. 1983; 27: 48395. showed similar efficacy with the old 6-capsule LNG 7. Sivin I. International experience with Norplant and Nor- subdermal system (Norplant®) in term of birth plant II contraceptive implants. Stud Fam Plann. 1988; 19: 81-94. control. Both implants system also have similar ® 8.Gu S, Du M, Zhang L, Liu Y, Wang S, Sivin I. A five-year tolerability profile. Jadena is easier to insert and evaluation of Norplant II implants in China. Contracept. remove than Norplant®. 1994; 50: 27-34. 9. Affandi B, Santoso SSI, Djajadilaga, Hadisaputro W, Moeloek FA, Prihastono J, et al. Five years experience with Norplant. REFERENCES Contracept. 1987; 36: 417-28. 1. Brache V, Faundes A, Johansson E, Alvarez F. Anovulation, 10.Sivin I, Alvarez F, Mishell DR Jr, Darney P, Wan L, Brache inadequate luteal phase and poor sperm penetration in cer- V, et al. Contraception with two levonorgestrel rod implants. vical mucus during prolonged use of Norplant implants. A 5-year study in the United States and Dominican Republic. Contracept. 1985; 31: 261-73. Contracept. 1998; 58: 275-82. 2. Croxatto HB, Diaz S, Salvatierra AM, Morales P, Ebensperger 11. Sivin I, Mishell DR Jr, Darney P, Wan L, Christ M. Levonor- C, Brandeis A. Treatment with Norplant subdermal implants gestrel capsule implants in the United States: a 5-year study. inhibits sperm penetration through the cervical mucus in Obstet Gynecol. 1998; 92: 337-44. vitro. Contracept. 1987; 36: 193-201. 12. Coukell AJ, Balfour JA. Levonorgestrel sub dermal implants. 3. Brache V, Alvarez-Sanchez F, Faundes A, Tejada AS, Cochon A review of contraceptive efficacy and acceptability. Drugs. L. Ovarian endocrine function through five years of conti- 1998; 55: 861-87. nuous treatment with Norplant subdermal contraception 13. Singh K, Viegas OA, Ratnam SS. Bleeding patterns and ac- implants. Contracept. 1990; 41: 169-77. ceptability among Norplant users in Singapore. Sing Med J. 4. Faundes A, Brache V, Tejada AS, Cochon L, Alvarez-Sanchez 1989; 30: 145-7. F. Ovulatory dysfunction during continuous administration 14. Shoupe D, Mishell DR Jr, Bopp BL, Fielding M. The signifi- of low- dose levonorgestrel by subdermal implants. Fertil cance of bleeding patterns in Norplant implant users. Obstet Steril. 1991; 56: 27-31. Gynecol. 1991; 77: 256-60. Vol 4, No 4 October 2016 A randomized five year comparative study 197

15. Vekemans M, Delvigne A, Pesmans M. Continuation rates 20. Klavon SL, Grubb GS. Insertion site complications during the with a levonorgestrel-releasing contraceptive implant (Nor- first year of Norplant use. Contracept. 1990; 41: 27-37. plant). A prospective study in Belgium. Contracept. 1997; 21. Shen Q, Lin D, Jiang X, Li H, Zhang Z. Blood pressure changes 56: 291-9. and hormonal contraceptives. Contracept. 1994; 50: 131- 16. Dunson TR, Krueger SL, Amatya RN. Risk factors for dis- 41. continuation of Norplant implant use due to menstrual problems. Adv Contracept. 1996; 12: 201-12. 22.Sivin I, Viegas O, Campodonico I, Diaz S, Pavez M, Wan L, et al. Clinical performance of a new two-rod levonorgestrel 17.Chaudhury N, Gupta AN, Hazra MN, Hingorani V, Kochhar contraceptive implant: a three-year randomized study with M, Kodkany BS, et al. Phase III-clinical trial with Norplant-2 Norplant implants as controls. Contraception. 1997; 55: 73- (covered rods). Report of a 24-month study. National Pro- 80. gramme of Research in Human Reproduction. Division of Human Resource Development Research Indian Council of 23. Fisher AA, Prihartono J, Tuladhar J, Hoesni RH. An assess- Medical Research Ansari Nagar, New Delhi, India. Contra- ment of Norplant removal in Indonesia. Stud Fam Plann. cept. 1998; 38: 659-73. 1997; 28: 308-16. 18. Biswas A, Leong WP, Ratnam SS, Viegas OA. Menstrual 24. Misra JS, Engineer AD, Tandon P. Cervical cytology associ- bleeding patterns in Norplant-2 implant users. Contracept. ated with levonorgestrel contraception. Acta Cytol. 1995; 1996; 54: 91-5. 39: 45-9. 19. Dal’Ava N, Bahamondes L, Bahamondes MV, de Oliveira Santos A, Monteiro I. Body weight and composition in users of levonorgestrel-releasing intrauterine system. Contracept. 2012; 86: 350-3. Indones J 198 Wiweko et al Obstet Gynecol

Research Article

The Outcome on Conservative Surgical Treatment of Adenomyosis Luaran Operasi Konservatif bagi Penderita Adenomiosis

Budi Wiweko, Ario Legiantuko, Achmad Kemal, Gita Pratama, Herbert Situmorang, Kanadi Sumapraja, Muharam Natadisastra, Andon Hestiantoro Department of Obstetrics and Gynecology Faculty of Medicine Universitas Indonesia/ Dr. Cipto Mangunkusumo General Hospital Jakarta

Abstract Abstrak

Objective: To understand the outcome on conservative surgical Tujuan: Untuk mengetahui keberhasilan operasi secara konservatif treatment of adenomyosis. bagi penderita adenomiosis. Methods: A retrospective cohort study followed for 2 years from Metode: Penelitian ini menggunakan studi restropektif yang diikuti 2010 to 2012 of women with adenomyosis were diagnosed by selama 2 tahun mulai tahun 2010-2012 pada pasien adenomiosis transvaginal sonography and confirmed histologically. Subjects di- yang diagnosis berdasarkan pemeriksaan sonografi transvaginal dan vided into women who were treated by adenomyosis resection dibuktikan secara histologi. Subjek dibagi menjadi dua kelompok, (with/without Osada’s technique) and who were underwent hys- yaitu yang ditangani dengan reseksi adenomiosis (dengan/tanpa terectomy. teknik Osada) dan yang ditangani dengan histerektomi. Results: After the surgery, as many as 40 patients (81.63%) did not Hasil: Setelah dilakukan operasi, 40 pasien (81,63%) tidak lagi feel any pain (VAS 0), and 9 patients (18.37%) still felt pain. For the merasakan nyeri (VAS 0), dan 9 pasien (18,37%) masih merasakan fertility outcome, we had 8 patients (20.51%) getting pregnant natu- nyeri. Untuk keberhasilan kehamilan, 8 pasien (20,51%) hamil secara rally without any fertility intervention. Two patients (5.13%) had alami tanpa intervensi kesuburan apa pun, dan 2 pasien (5,13%) ber- successfully conceived by IVF. According to the type of surgery, from hasil hamil dengan teknik fertilisasi in vitro (FIV). Berdasarkan tipe 8 natural pregnancy, 7 patients (87.50%) was underwent conven- operasi adenomiosis, dari 8 kehamilan alami, 7 pasien (87,50%) di- tional resection of adenomyosis and 1 patients (12.50%) underwent lakukan dengan reseksi adenomiosis secara konservatif dan 1 pasien Osada’s procedures. Two patients who were conceived by IVF, both (12,50%) dengan Osada. Dua pasien yang berhasil hamil dengan FIV, of them were underwent Osada’s resection. reseksi adenomiosis dilakukan dengan teknik Osada. Conclusion: Adenomyosis resection both conservative or Osada’s Kesimpulan: Reseksi adenomiosis, baik konservatif maupun Osada procedures actually has a better outcome for relieving pain; there- memiliki keberhasilan yang baik dalam menghilangkan keluhan nyeri fore, some patients can still have a child. dan beberapa pasien dapat tetap memiliki anak. [Indones J Obstet Gynecol 2016; 4-4: 198-202] [Maj Obstet Ginekol Indones 2016; 4-4: 198-202] Keywords: adenomyosis resection, conventional resection, infertil- Kata kunci: infertilitas, reseksi adenomiosis, reseksi konvensional, ity, Osada’s procedure prosedur Osada

Correspondence: Budi Wiweko, [email protected]

INTRODUCTION days, many women at reproductive age suffers from adenomyosis. Some studies said this condi- Bird et al. defines adenomyosis as the benign inva- tion was due to the changes of lifestyle.2 sion of endometrium into the myometrium, pro- ducing a diffusely enlarged uterus which micro- The symptoms are various, including dysmenor- scopically exhibits ectopic, non-neoplastic, endo- rhea (80%) as the most frequent symptom pre- metrial glands, and stroma surrounded by the sented by the patients. Other symptoms are pelvic hypertrophic and hyperplastic myometrium.1,2 The pain (50%), infertility (40%), and menstrual dis- disease has been recognized since the end of the turbance (20%). Apart from that, there are less 19th century, but during the first quarter of the 20th often complaints such as menorrhagia, dyspareu- century, all mucosal invasions in the peritoneal nia, suprapubic pain, uterus enlargement, and cavity or within the uterine walls were labeled as some women do not have any complaints.4,5 ’adenomyomas’.3 The effective treatment requires more radical The incidence of this disease usually occurs to resection of the affected tissues. It is still contro- women at perimenopause period; however, nowa- versial between the radical procedure with hyster- Vol 4, No 4 October 2016 Outcome on conservative surgical treatment 199 ectomy and conservative surgery by adenomyosis tween January 2010 and November 2012, 47 pa- resection.3,6,7 Since 1952, surgery for adenomyosis tients (48.96%) ran into hysterectomy. Almost all performed with resection of adenomyosis, fol- patients diagnosed with adenomyosis, presented lowed by the reconstruction of the uterus wall severe dysmenorrhea (having Visual Analog Scale/ (called by conservative surgery). In 2010, Hisao VAS >7) and some patients said about dyspareunia. Osada had introduced surgical technique initiated Thirty-three patients caused by primary infertility by placing a temporary tourniquet around the went through adenomyosis resection. On the other lower uterine segment of the uterus to prevent the hands, all patients performed hysterectomy al- massive bleeding. The operator would open the ready had married, the average age was 45.52 (SD uterus boldly all the way down to the endometrial 3.61) years old, 37 patients already had at least 1 lining. The non-demarcated adenomyotic tissue child, and 1 patient experienced primary infertility was excised leaving a centimeter on the endo- for 10 years; but, she already agreed to have hys- metrial side and a centimeter on the serosal (outer) terectomy. Age of patients undergoing either hys- side of the uterus. Furthermore, the remaining terectomy or adenomyosis resection was ranged muscle of this debulked adenomyotic uterus mus- between 28 and 49 years old, which all of them culature would be closed with many layers of su- tures, all non-overlapping flaps, to prevent the risk still had regular menstrual period. of rupture.7 Therefore, this study aims to under- Among 49 patients carrying out adenomyosis stand the outcome on conservative surgical treat- resection, 31 of them (32.29%) were held conven- ment of adenomyosis. tional adenomyosis resection and the mean age of them was 35.83 (SD 3.51) years old. Eighteen pa- METHODS tients (18.75%) underwent surgery by Osada’s procedure with mean age were 33.63 (SD 3.48) This retrospective cohort study was performed at years old. Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia. All medical records of patients with a diagnosis of adenomyosis between January 2010 Table 1. Mean Age of Subjects based on Surgery Method and November 2012 were reviewed. All patients Surgery n (%) Age already underwent laparotomy adenomyosis re- Method (Mean (SD)) section with or without GnRH agonist as adjuvant Hysterectomy 47 (48.96) 45.52 (3.61) treatment. Resection Conventional 31 (32.29) 35.83 (3.51) We collected 96 patients diagnosed adenomyo- Osada 18 (18.75) 33.63 (3.48) sis. They had already done surgery treatment; whereas, 49 patients underwent adenomyosis re- section and the remaining of 47 patients under- Looking at the symptoms, dysmenorrhea was went hysterectomy. the most common complaints (69.39%) of patients Diagnosis of adenomyosis was confirmed with to seek treatment in hospital. While, other symp- transvaginal sonography and histological evalu- toms such as pelvic pain, dyspareunia, and bleed- ation after surgery. About 18 women undertook ing became less common. Regarding to the fertility adenomyosis resection by Osada’s procedure. problem, 33 patients (67.35%) came with primary Meanwhile, 31 women carried out conventional infertility, 6 patients (12.24%) with secondary in- adenomyosis resection. All surgery procedures fertility, and 10 patients (20.41%) with no fertility were well documented on medical records. problem. Informed consent was obtained and approved Before surgery, most patients presented with by The Ethical Committee, Faculty of Medicine dysmenorrhea with the VAS of 7-10. One year after Universitas Indonesia. surgery, 40 patients (81.63%) did not feel pain (VAS 0) and there were no patients complaining with persistent pain. Besides, 9 patients (18.37%) RESULTS were still perceived less pain without further treat- Of 96 patients who diagnosed adenomyosis be- ment. Indones J 200 Wiweko et al Obstet Gynecol

Table 2. Clinical Characteristics and Symptoms after Surgery Variables n (%) Parity 0 37 (75.51) 1 6 (12.24) 2 4 (8.16) 3 2 (4.08) Symptoms Dysmenorrhea 34 (69.39) Pelvic pain 7 (14.29) Dysmenorrhea and dyspareunia 4 (8.16) Dysmenorrhea and pelvic pain 3 (6.12) Hemorrhage 1 (2.04) Fertility Primary infertility 33 (67.35) Secondary infertility 6 (12.24) No infertility 10 (20.41) Symptoms after operation No symptom 40 (81.63) Persistent symptoms (persistent VAS) 0 (0.00) Decreased symptoms (VAS<2) 9 (18.37)

The duration of infertility was 4.94 (SD 3.52) DISCUSSION years for primary infertility and 7.33 (4.68) years for secondary infertility. Concerning to the result Adenomyosis may be described as a diffuse inva- sion of endometrial element into the uterine myo- of fertility, there were 8 patients (20.51%) con- metrium. Adenomyosis differs from fibromyoma- ceived naturally without fertility intervention, 2 tous growth; whereas, there is no discrete borders patients were successfully delivered by cesarean between the normal uterine tissue and the lesion. section (CS), and no events of uterine rupture. Until Therefore, a clear dissection plane is difficult to es- finishing this study, four patients were still con- tablish so that this procedure is challenging.3,7 tinuing their pregnancy and having more than 20 weeks of gestational age. Unfortunately, the 2 pa- In addition to infertility, high grade of adeno- tients who conceived naturally experienced mis- myosis also causes severe dysmenorrhoea and carriage at 3 months of pregnancy. Two patients hypermenorrhoea, which adversely affects the (5.13%), which had been successfully prepared by woman’s well-being. The management for the in vitro fertilization (IVF), was delivered by CS. latter two symptoms includes long-term hormonal According to the surgery method, 8 women who therapy, analgesics, and finally hysterectomy. For succeeded natural pregnancy, 7 patients (87.5%) those who wish to preserve reproductive function, were performed conventional adenomyosis resec- the surgical management of severe adenomyosis tion and 1 patient (12.5%) was underwent the cases is particularly difficult because the operator Osada’s procedure resection. Two patients who has to excise diffusely involving tissue and prevent were conceived by IVF, both of them were resected the occurrence of uterine rupture in the event of though Osada’s procedure. pregnancy.3,4,8

Table 3. Fertility Outcome based on Surgery Method Pregnancy n (%) Osada Procedure (%) Conventional resection (%) Natural pregnancy 8 (20.51) 1 (12.50) 7 (87.50) Pregnancy with IVF 2 (5.13) 2 (100.00) 0 (0.00) Unpregnant 29 (74.36) Vol 4, No 4 October 2016 Outcome on conservative surgical treatment 201 The requirement of adenomyosis surgery for the who conceived with IVF procedure and underwent purpose of preserving reproductive functions is as cesarean section delivery. Among these two pa- follows. Firstly, it is ideal if tubal patency can be tients who became pregnant by natural concep- retained to allow for natural pregnancy. Secondly, tion; unfortunately, they had miscarriage at 3 the uterine cavity must be retained intact in order months of pregnancy. This is in accordance with to assure implantation. Thirdly, the uterine wall study by Lukes, et al., which stated that the risk of must be properly reconstructed to enable it to sus- miscarriage in adenomyosis was four times higher tain fetal growth following conception. In other than women without adenomyosis.9,12 words, the operator must reconstruct the uterine The low percentage of pregnancy after surgery wall which can endure the thin lines associated was due to several reasons. Possible causes were with the expansion of the uterine cavity. In the end, firstly, postoperatively, almost all patients did not it results the development of pregnancy.7,9,10 come back to the follow up on their fertility prob- There is also the problem on recurrence of the lem. Secondly, fertility work-up was not performed disease. In this case, we had to observe the patient completely before the surgery because most of the routinely and perform ultrasound examination to main complaints of patients coming to the hospital investigate whether there was a new mass. Unfor- was severe pain. Among 7 patients having success- tunately, this was not a routine procedure in our ful pregnancy (more than 20 weeks of gestational hospital. Up to a year follow-up, all patients who age), only 2 patients with IVF pregnancy came for carried out resection did not complain about se- antenatal care at our hospital. vere dysmenorrhea.5 Some patients (9 patients) still presented pain CONCLUSION on the low VAS score so that they did not obtain Adenomyosis resection offers new hope to patients the analgesic medication. Among 49 patients un- who want to preserve their uterus for several rea- dergoing surgery, 22 of them were given GnRH sons. Adenomyosis resection, either conventional agonist (Tapros®), 10 patients did not receive any or Osada’s procedure actually has better outcomes treatment; however, we did not have any informa- for pain relief and similar result for the heredity. tion about other 17 patients. Both group of patients Fertility work-up (both husband and wife) and who were given GnRH agonist or not had no dif- some reproductive interventions, such as intra- ferent outcome on the pain score measured by VAS uterine insemination (IUI) or IVF may increase the after surgery.11 probability of pregnancy for women who suffer Based on the observation on two methods of from adenomyosis. adenomyosis resection, the first was adenomyosis conventional resection (performed for 31 patients ACKNOWLEDGEMENTS (32.29%)) compared to Osada procedure (per- formed for 18 patients (18.75%)). We did not find The author would like to express our gratitude to any significantly different outcome between these medical record staffs and to dr. Liva Wijaya, dr. surgical techniques. Close observation shoud per- Johnny Judio, and dr. Matthew M for their assis- form for many years into the future to conclude tance in preparing this manuscript. the final outcome between these two procedures. Studies that had been conducted by Osada in 2011, the ten-year observation after Osada procedure REFERENCES which included 104 subjects showed excellent re- 1.Bergholt T, Berendt N, Jacobsen M, Hertz JB, et al. Preva- sults in the likelihood of adenomyosis recur- lence and risk factors of adenomyosis at hysterectomy. Hum rence.3,6,7 Reprod. 2001; 16(11): 2418-21. 2.Dueholm, Margit, Lundorf, Erik, et al. Transvaginal ultra- Regarding to the result of fertility, among 49 pa- sound or MRI for diagnosis of adenomyosis. Curr Opin tients, 33 of them (67.35%) came with primary in- Obstet Gynecol. 2007; 19(6): 505-12. fertility, 6 patients (12.24%) had secondary infer- 3. Takeuchi H, Kitade M, Kikuchi I, et al. Laparoscopic ade- tility problem. After resection performed, 8 pa- nomyomectomy and hysteroplasty: a novel method. J Minim Invasiv Gynecol. 2006; 13: 150-4. tients (20.51%) had a natural pregnancy with 2 of 4. Matalliotakis IM, Katsikis IK, Panidis DK. Adenomyosis: them underwent a caesarean delivery and their ba- what is the impact on fertility? Curr Opin Obstet Gyn. 2005; bies were in good condition. Two patients (5.13%) 17(3): 261-4. Indones J 202 Wiweko et al Obstet Gynecol

5. Ferrero S, Camerini G, Menada MV, Biscaldi E, RAgni N, Re- 9. Tremellen K, Thalluri V. Response: Impact of adenomyosis morgida V. Uterine adenomyosis in persistence of dysme- on pregnancy rates in IVF treatment. Reprod Biomed On- norrhea after surgical excision of pelvic endometriosis and line. 2013; 26(3): 299-300. colorectal resection. J Reprod Med. 2009; 54(6): 366-72. 10. Ofir K, Sheiner E, Levy A, Katz M, Mazor M. Uterine rupture: 6. Rajuddin, Jacoeb TZ. Penanganan adenomiosis dengan re- differences between a scarred and an unscarred uterus. Am seksi laparotomik pada perempuan infertile. Indones J J Obstet Gynecol. 2004; 191: 425-9. Obstet Gynecol. 2008; 32(1): 22-5. 11. Surrey ES, Silverberg KM, Surrey MW, WB. S. Effect of pro- 7. Osada H, Silber S, Kakinuma T, Nagaishi M, Kato K, O. K. longed gonadotropin-releasing hormone agonist therapy on Surgical procedure to conserve the uterus for future preg- nancy in patients suffering from massive adenomyosis. Re- the outcome of in vitro fertilization-embryo transfer in pa- prod Biomed Online. 2011; 22: 94-9. tients with endometriosis. Fertil Steril. 2002; 78: 699-704. 8. Jean H B, Tetrokalasvili M, Fogel J, Hsu CD. Characteristics 12. Wada S, Kudo M, Minakami H. Spontaneous uterine rupture associated with postoperative diagnosis of adenomyosis or of a twin pregnancy after a laparoscopic adenomyomec- combined adenomyosis with fibroids. Int J Gynecol Obstet. tomy: a case report. J Minim Invasiv Gynecol. 2006; 13: 166- 2013; 122(2): 112-4. 8. Vol 4, No 4 October 2016 Anti-müllerian hormone level 203

Research Article

Anti­Müllerian Hormone Level in Laparoscopic Cystectomy Kadar Anti Müllerian Hormon pada Laparoskopi Kistektomi

Edwin Budipramana, Nusratuddin Abdullah, Telly Tessy Department of Obstetrics and Gynecology Faculty of Medicine Universitas Hasanuddin/ Dr. Wahidin Sudirohusodo Hospital Makassar

Abstract Abstrak

Objective: To evaluate the impact of laparoscopic cystectomy using Tujuan: Mengevaluasi pengaruh laparoskopi kistektomi dengan tek- cautery and suturing technique on the ovarian reserve represented nik kauter dan penjahitan terhadap cadangan ovarium yang direpre- by the level of Anti-Müllerian Hormone (AMH) serum. sentasikan oleh kadar serum hormon anti mullerian (AMH). Method: This used prospective cohort study design conducted in Metode: Penelitian dengan rancangan kohort prospektif dilaksa- Dr. Wahidin Sudirohusodo Hospital, Department of Obstetrics and nakan di RS dr. Wahidin Sudirohusodo, Departemen Obstetri dan Gi- Gynecology, Faculty of Medicine Universitas Hasanuddin, Makassar, nekologi Fakultas Kedokteran Universitas Hasanudin (Unhas) di from November 2014 to October 2015. We got total samples of 60 Makassar mulai November 2014 hingga Oktober 2015. Didapatkan subjects divided into cautery and suturing group. Anti-Mullerian sampel sebanyak 60 subjek yang memenuhi kriteria dan dimasukkan hormone serum test was examined on all subjects pre and post pada kelompok kauter dan penjahitan. Semua subjek dilakukan pe- laparoscopic cystectomy. meriksaan AMH pre dan post laparoskopi kistektomi. Result: The result indicated a significant decrease of AMH level Hasil: Penelitian menunjukkan penurunan yang bermakna dari kadar undergoing laparoscopic cystectomy both cautery and suturing AMH pada sampel yang menjalani laparoskopi kistektomi dengan technique; whereas, more dominant results were showed in the teknik kauter maupun penjahitan, dengan hasil yang lebih dominan cautery group (p<0.05). In the 95% confident interval (CI), the mean pada kelompok kauter (p<0,05). Pada nilai interval kepercayaan (IK) decrease of cautery group was 0.87 ng/ml and 0.31 ng/ml for 95% didapatkan rata-rata penurunan pada kelompok kauter dan suturing group. Both groups showed greater decrease in bilateral penjahitan sebesar 0,87 ng/ml dan 0,31 ng/ml. Pada kedua kelompok cyst, endometriotic type of cyst, and the cyst diameter of less than 5 didapatkan penurunan AMH yang lebih besar pada kista bilateral, tipe cm; although these differences were not statictically significant kista endometriosis, dan ukuran kista <5 cm, namun perbedaan antar (p>0.05). kedua kelompok tidak bermakna secara statistik (p>0,05). Conclusion: The decline in the number of ovarian reserve as Kesimpulan: Penurunan jumlah cadangan ovarium yang digam- described by the reduction of AMH level occurs significantly in both barkan oleh AMH terjadi secara signifikan pada kedua prosedur cauterization and suturing technique, which are more dominant hemostasis dengan energi panas kauterisasi dan penjahitan, dengan reduction in the cauterization group. penurunan lebih dominan pada kelompok kauterisasi. [Indones J Obstet Gynecol 2016; 4-4: 203-207] [Maj Obstet Ginekol Indones 2016; 4-4: 203-207] Keywords: Anti-Müllerian Hormone, laparoscopic cystectomy, ova- Kata kunci: cadangan ovarium, hormon anti-mullerian, laparoskopi rian reserve kistektomi

Correspondence: Edwin Budipramana, [email protected]

INTRODUCTION Generally, two types of ovarian cyst usually found are functional cyst and endometriosis. Each Ovarian cyst is the most common form of mass on type of cyst has its own unique characteristics so ovarium. The incidence of ovarian cyst was re- that the operator can destroy the ovaries ported between 5 and 15 percent of all the gyne- differently during performing the laparotomy or 1 cological tumor. laparoscopic cystectomy. In patients with ovarian The clinicians usually diagnose ovarian cyst cyst who undergo laparoscopic cystectomy, there through pelvic examination and ultrasound (USG) will be normal ovarian tissue damaged during the imaging modalities; then, they proceed with tumor surgical procedure, either due to sticky tissues or marker assessment to detect the possibility of ma- cauterization procedure. Normal ovarian tissue lignancy. After diagnosing, they manage the ova- should be maintained as well as possible because rian cyst through either conservative observation it is related to the ovarian ability to maintain the or surgery.1 ovulation.2 Indones J 204 Budipramana et al Obstet Gynecol Anti-Müllerian Hormone (AMH) is hormone pro- METHODS duced by the granulosa cells of primary ovarian fol- This study was held in Dr. Wahidin Sudirohusodo licles. The highest expression is during preantral as a teaching hospital with laparoscopic surgery and antral follicles phase, and it will no longer be facility, Department of Obstetrics and Gynecology, detectable when the follicles undergo atresia. Anti- Faculty of Medicine, Universitas Hasanuddin, Müllerian Hormone serum level is strongly associ- Makassar, South Sulawesi. This study used a ated with the number of antral follicles, which de- prospective cohort study design from November scribe the number of remaining primordial follicles 2014 to October 2015. We obtained 60 women reserve. The reserve of primordial follicles can be suffering from ovarian cyst who had undergone used as an illustration of the ovulation induction laparoscopic cystectomy procedure. success.3 The more severe of damage to ovarian We examined AMH serum level thorugh blood. tissue after cauterization process during laparo- The blood samples were taken from each patient scopic cystectomy, the less number of normal fol- at the ventral region of the cubital cavity before licles left; therefore, AMH level will decline after and one month after the laparoscopic cystectomy surgery.4 During laparoscopic cystectomy proce- procedure. We analyzed using paired t-test for the dure, there is a chance for the damage of normal AMH serum level to compare the reduction quan- tity between cauterization and suturing group. We ovarian tissue because of heat cauterization. As a considered statitistically significant if p value less result of this procedure, the patients have an iatro- than 0.05. genic decline in the number of ovarian follicles causing premature menopause. Apart from that, AMH is used as a prognostic factor for induction of RESULTS ovulation in in-vitro fertilization; whereas, it needs We collected 60 samples fulfilling the inclusion 5 sufficient number of ripe ovarian follicles. criteria. They consisted of 30 samples who Over the last twenty years, AMH, Follicle Stimu- underwent intraoperative cauterization and the remaining 30 samples performing intraoperative lating Hormone (FSH), Estradiol (E2), and inhibin suturing. The characteristics of subjects include B serum level have been studied to describe the age, educational level, marital status, parity, cyst number of ovarian cells reserve. However, FSH, E , 2 location, type, size, and adhesion (table 1). and inhibin B serum markers are associated with negative feedback on the pituitary-ovarian axis, so Table 1 showed that subjects who had under- that the level of them will be fluctuated during gone cauterization technique generally were 20-40 years old (90%), most of them graduated from menstrual phase. Meanwhile, the AMH serum level senior high school (43%), had married (83.3%), is relatively stable during the cycle. In conclusion, and ever delivered more than or equal to 2 times the AMH serum can be used as the reliable marker (36%). The type of cyst was generally endome- for ovarian follicle reserve compared with other triosis (73.3%), located unilaterally (73.3%) with markers.2 size of 5-10 cm (60%), and the cyst did not show adhesion (70%). Meanwhile, subjects doing the This study is conducted on women sufferring suturing techniques were 20-40 years (93.3%), from ovarian cyst who had undergone laparoscopic educational level of senior high school (56.7%), cystectomy with intraoperative cauterization pro- had married (83.3%) with 1 parity (44%). Most of cedure. We compared between the pure suturing cyst typewas endometriosis (63.3%), located and without cauteterization technique. The AMH unilaterally (70.0%), with size less than 5 cm level serum on each patient was measured before (66.7%), and no adhesion (66.7%). The statistical surgery and continued by after surgery. The aim of result using Shapiro-wilk normality test, we this study is to determine the significant reduction obtained p value more than 0.05; therefore, there on the AMH level in both sample groups with dif- were no statistically significant differences in age, educational level, marital status, parity, cyst ferent techniques. location, type, size, and adhesion between cauterization and suturing group. Thus, both groups described fairly homogenous. Vol 4, No 4 October 2016 Anti-müllerian hormone level 205

Table 1. Characteristics of Subjects Technique Total Characteristics p Cauterization Suturing Age group (years old) 20-40 27 (90.0) 28 (93.3) 55 (91.7) 1.000 > 40 3 (10.0) 2 (6.7) 5 (8.3) Education Junior high school 5 (16.7) 5 (16.7) 10 (16.7) Senior high school 13 (43.3) 17 (56.7) 30 (50.0) 0.513 University 12 (40.0) 8 (26.7) 20 (33.3) Marital status Married 25 (83.3) 25 (83.3) 50 (83.3) 1.000 Unmarried 5 (16.7) 5 (16.7) 10 (16.7) Parity 0 8 (32.0) 5 (20.0) 13 (26.0) 1 8 (32.0) 11 (44.0) 19 (38.0) 0.558  2 9 (36.0) 9 (36.0) 18 (36.0) Cyst location Unilateral 22 (73.3) 21 (70.0) 43 (71.7) 0.774 Bilateral 8 (26.7) 9 (30.0) 17 (28.3) Cyst type Endometriosis 22 (73.3) 19 (63.3) 41 (68.3) 0.405 Simple 8 (26.7) 11 (36.7) 19 (31.7) Cyst size <5 cm 12 (40.0) 20 (66.7) 32 (53.3) 0.195 5-10 cm 18 (60.0) 10 (33.3) 28 (46.7) Adhesion Present 9 (30.0) 10 (33.3) 19 (31.7) 1.000 Not present 21 (70.0) 20 (66.7) 41 (68.3)

Table 2. The Difference of AMH Level Pre and Post Surgery According to Surgical Technique AHM Level (ng/ml) Technique Time p Mean SD Cauterization Pre surgery 3.56 3.10 0.011 Post surgery 2.69 2.39 Suturing Pre surgery 4.27 2.60 0.028 Post surgery 3.90 2.55

In cauterization group, the average AMH level value of 0.011 in the cauterization group and 0.028 pre surgery was 3.56 ng/ml; whereas, it decreased in the suturing group. It meant that there were to 2.69 ng/ml post surgery. In the suturing group, statistically significant difference of the AMH level the average pre surgery AMH level was 4.27 ng/ml; alteration either using cauterization or suturing while, the post surgery level was 3.9 ng/ml. techniques. Statistical result using paired t-test, we obtained p Indones J 206 Budipramana et al Obstet Gynecol Table 3. Mean Changes of AMH Level According to ng/ml and 1.00 ng/ml. In the group sized 5-10 cm, Surgery Technique the AMH level in the cauterization technique AMH Level (ng/ml) declined 1.11 ng/ml and 1.10 ng/ml in suturing Technique p Mean SD technique group. Independent t-test result pointed Cauterization 0.87 0.98 out p value more than 0.05 on cyst location, type, 0.005 adhesion, and size. There were not significantly Suturing 0.31 0.28 different in the reduction of AMH level between study groups. The average alteration in AMH level on the cauterization technique was 0.87; while, the suturing technique was 0.31. Statistical result using DISCUSSION independent t-test showed the p value of 0.005, it This study showed that the average reduction of meant that there was significant difference in AMH AMH level was greater in the cauterization group level between two groups. which was statistically significant (p <0.05). We Table 4 explained that in unilateral cyst, the also found that the average AMH serum level average decline of AMH level in the cauterization dropped more largely on the sample with bilateral technique was 1.14 ng/ml and 1.00 ng/ml for cyst (mean 1.25 ng/ml), endometriosis cyst (mean suturing technique; whereas, for bilateral cyst, the 1.23 ng/ml), presence of intraoperative adhesion average decline of AMH level in the cauterization (mean 1.22 ng/ml) and cysts sized <5 cm (mean technique was 1.25 ng/ml and 1.11 ng/ml in the 1.25 ng/ml); however, they were not statistically suturing technique. Based on endometriosis cyst significant (p>0.05). Another study by Celik, et al. type, the average decline of AMH level in the also found that decreasing level of AMH was seen cauterization technique was 1.23 ng/ml and 1.05 in bilateral, endometriosis cysts sized <5 cm. In ng/ml in the suturing technique group. On the small bilateral cyst, it was likely that the number simple cyst type, the average change of AMH level of healthy ovarian tissue damaged or taken away in both cauterization and suturing techniques was would be a lot through observing the reduction of AMH level.6 1.00 ng/ml each. Based on the presence intra- operative adhesion, the average decline of AMH Intraoperative cauterization procedure uses level in the cauterization and suturing technique heat energy to burn tissues during hemostasis was 1.22 ng/ml and 1.10 ng/ml. Based on the cyst process. Heat from cauter can damage the size group (<5cm), the AMH level in the cauteriza- surrounding healthy ovarian tissue and cause more tion and suturing technique dropped into 1.25 primordial follicles damage. It is illustrated thorugh

Table 4. Difference of Homone Level According to Cyst Location, Adhesion, Size, and Type Cauterization Suturing Cyst p nMean (SD) n Mean (SD) Location Unilateral 22 1.14 (0.35) 21 1.00 (0.00) 0.083 Bilateral 8 1.25 (0.46) 9 1.11 (0.33) 0.485 Type Endometriosis 22 1.23 (0.43) 19 1.05 (0.23) 0.107 Simple 8 1.00 (0.00) 11 1.00 (0.00) - Adhesion Present 9 1.22 (0.44) 10 1.10 (0.32) 0.493 Not present 21 1.14 (0.36) 20 1.00 (0.00) 0.083 Size <5 cm 12 1.25 (0.45) 20 1.00 (0.00) 0.082 5 - 10 cm 18 1.11 (0.32) 10 1.11 (0.32) 0.931 Vol 4, No 4 October 2016 Anti-müllerian hormone level 207 the higher AMH level reduction.7 In the suturing CONCLUSION AND RECOMMENDATION group, AMH reduction may occur because the operator accidentally drawed the ovarian The decline in the number of ovarian reserve as parenchym during the excision of cyst wall. described by the reduction of AMH level occurs According to Roman, it generally happened significantly in both cauterization and suturing because there was no clear barrier between cyst technique, which are more dominant reduction in wall lining and ovarian cortex histologically. the cauterization group. This suggests that t Therefore, it is estimated that the cyst wall excision cauterization using heat energy causes wide range can cause ovarian reserve reduction.8 of ovarian tissue damage. Further study should be conducted to evaluate other causes of Anti- Most of the ovarian cyst patients in this study Müllerian hormone level reduction other than were 20-40 years old. This was according to study iatrogenic factors, such as surgery. by Tzadik which they stated that the peak incidence of ovarian cyst was on the reproductive aged women.9 In terms of education, the majority REFERENCES of subjects was well educated. It was related to the 1. Schorge J, Schaffer J, Halvorson L, et al. Pelvic mass: Cystic ovarian cyst characteristic symptoms, namely ovarian masses. Williams Gynecology. Texas: McGraw-Hill; asymptomatic for functional/simple cyst, or cyclic 2008: 210-2. pain for endometriosis cyst. Patients with sufficient 2. Hwu YM, Wu SY, Li SH, et al. The impact of endometrioma education will have good self-sensibility to feel the and laparoscopic cystectomy on serum anti-Müllerian hormone levels. Reprod Biol Endocrinol. 2011; 9: 80. disorder and they will immediately check 3. Practice Committee of the American Society to Reproduc- themselves despite of slight complaint. tive Medicine. Testing and interpreting measures of ovarian reserve: A committee opinion. Fertil Steril. 2012; 98(6): The most common cyst found in this study was 1407-19. endometriosis cyst. This was in accordance with 4. Visser JA, de Jong FH, Laven JS, et al. Anti-Müllerian the highest incidence of endometriosis in hormone: A new marker for ovarian function. Reprod. reproductive aged women, both married and 2006; 131(1): e1-9. unmarried, where major symptoms complaint 5.Raffi F, Metwally M, Amer S. The impact of excision of ovarian endometrioma on ovarian reserve: A systematic were dysmenorrhea, chronic pelvic pain, and review and meta-analysis. J Clin Endocrinol Metab. 2012; infertility.2 97(9): 3146-54. 6.Celik HG, Dogan E, Okyay E et al. Effect of laparoscopic Pre surgery AMH level obtained were varied. excision of endometriomas on ovarian reserve: serial According to La Marca, AMH level was stable changes in the serum antimullerian hormone levels. Fertil throughout the menstrual cycle compared with Steril. 2012; 97(6): 1472-8. other ovarian reserve markers; although the result 7. Massarweh NN, Cosgriff N, Slakey DP. Electrosurgery: showed various among individuals. It occured History, principles, and current and future uses. Am Coll Surg. 2005; 202(3): 520-30. because there was wide variability of the ovarian 8. Roman H, Kitajima M, Khan KN, et al. Anti-Müllerian reserve in each individual. Currently, we still need hormone level and endometrioma ablation using plasma further study in AMH level according to race, body energy. JSLS. 2014; 18(3). mass index (BMI), and exposure to cigarette 9. Tzadik M, Purcell K. Benign disorders of the ovaries dan smoke.10 oviducts. Current diagnosis and treatment: Obstetrics and gynecology 10th ed. USA: McGraw-Hill; 2007: 654-61. 10. LaMarca A, Grisadi V, Griesinger G. How much does AMH really vary in normal women? Int J Endocrinol. 2013; 959487. Indones J 208 Juniarto and Moegni Obstet Gynecol

Research Article

Comparison of the Levator Hiatal Area Perbandingan Area Hiatal Levator Ani

Muhammad E Juniarto, Fernandi Moegni Department of Obstetrics and Gynecology Faculty of Medicine Universitas Indonesia/ Dr. Cipto Mangunkusumo Hospital Jakarta

Abstract Abstrak

Objective: To determine the relationship of the levator hiatal area Tujuan: Untuk mengetahui hubungan area hiatal otot levator ani pe- among nulliparous, primiparous, and multiparous women so that rempuan nulipara, primipara dan multipara saat istirahat/kontraksi we can assess the prevalence of avulsion. dan manuver Valsalva serta mengetahui prevalensi kejadian avulsi. Method: A cross-sectional study design was used by evaluating the Metode: Penelitian ini menggunakan studi potong lintang dengan transperineal ultrasound results of all nulliparous, primiparous, and melihat hasil pemeriksaan USG transperineal yang dilakukan pada multiparous women in the Obstetrics and Gynecology Clinic of pasien perempuan nulipara, primipara dan multipara yang datang ke Dr. Cipto Mangunkusumo hospital from May to December 2015. We poli Obstetri dan Ginekologi RSUPN Dr. Cipto Mangunkusumo pada analyzed the data through SPSS using one way ANOVA to compare bulan Mei-Desember 2015. Kami melakukan analisis data dengan the levator hiatal dimension among the groups of women during SPSS menggunakan one way ANOVA untuk membandingkan area Valsava maneuver and at rest. levator hiatal antara kelompok pasien selama manuver Valsalva dan Result: There were significant differences in levator hiatal area saat istirahat. among nulliparous, primiparous, and multiparous women during Hasil: Terdapat perbedaan bermakna untuk area hiatal otot levator Valsalva maneuver and at rest, which the mean (SD) was 22.26 ani pada saat Valsalva maupun istirahat untuk ketiga kelompok (5.45) cm2 (p=0.028) and 10.70 (2.26) cm2 (p=0.012), respectively. penelitian dengan (p=0.028 dan p=0.012). Saat Valsalva, perbedaan Levator ani muscle avulsion was occurred in 1 out of 46 (2.2%) area hiatal otot levator ani ditemukan pada kelompok nulipara dan women from the primiparous and multiparous group. multipara dengan perbedaan rerata (standar deviasi) yaitu 22,26 2 Conclusion: There are significant differences in levator hiatal area (5,45) cm . Saat istirahat, perbedaan area hiatal otot levator ani dite- during Valsalva and at rest among the groups. mukan pada kelompok nulipara dan multipara dengan perbedaan rerata (standar deviasi) yaitu 10,70 (2,26) cm2. Avulsi otot levator ani [Indones J Obstet Gynecol 2016; 4-4: 208-211] terjadi pada 1 dari 46 (2,2%) pada perempuan primipara dan perem- Keywords: avulsion, levator hiatal area, multiparous, nulliparous, puan multipara. primiparous Kesimpulan: Terdapat perbedaan bermakna untuk area hiatal otot levator ani pada saat maneuver Valsalva maupun istirahat untuk ketiga kelompok penelitian. [Maj Obstet Ginekol Indones 2016; 4-4: 208-211] Kata kunci: area hiatal levator ani, avulsi, multipara, nulipara, primi- para

Correspondence: Muhammad Eric Juniarto, [email protected]

INTRODUCTION of vaginal childbirth2 affecting between 13% and 36% of women. In general, it happens after the first Pelvic floor dysfunction becomes major public vaginal delivery.2-9 In nulliparas, no avulsions were health problem, whereas, around 23% of women observed.10 suffer from this condition worldwide. Pelvic floor dysfunction significantly decreases the quality of A levator avulsion results from the detachment life due to many symptoms, such as constipation, of inferior pubic rami on puborectalis muscle.11 urinary or anal incontinence, chronic pelvic pain, The striated muscles of levator ani form an essen- and urogenital prolapse.1 tial component of structural support mechanism in An important component of pelvic floor system the pelvic floor. Unlike other skeletal muscles, the is levator ani muscle; therefore, trauma to this levator ani muscle differs because it maintains con- muscle is related to pelvic floor disorders. Avulsion stant tone, except during voiding, defecation, and of the levator ani muscle is a common consequence the Valsalva maneuver. It has the capability to con- Vol 4, No 4 October 2016 Comparison of the levator hiatal area 209 tract rapidly during sudden increase of abdominal tribution on levator hiatal area were normal pressure, for example on a cough or sneeze or among all groups. The ANOVA result showed the physical activity; thereby, it will reduce the risk of significant differences on levator hiatal area among incontinence and pelvic organ prolapse (POP). nulliparous, primiparous, and multiparous women Paradoxically, it has to stretch during parturition during Valsalva maneuver (p=0.012). even beyond its limits in order to allow the passage of baby. However, it has to contract after delivery to preserve the normal function.12 Levator anal Table 2. Comparisons of Levator Hiatal Dimensions muscle is very susceptible to the stretch-induced Measured at Valsalva Maneuver injury. During the stretch, the extent of injury is NMean (SD) p value proportional to the work performed on the mus- Nulliparous group 23 17.72 (4.93) 0.012 cle.13 Therefore, this study aims to determine the Primiparous group 23 18.69 (5.37) relationship of the levator hiatal area among nulli- parous, primiparous, and multiparous women so Multiparous group 23 22.26 (5.45) that we can assess the prevalence of avulsion. Table 3 presented levator hiatal dimension mea- METHOD sured at rest. Among all groups, levator hiatal measurement was normally distributed. The A cross sectional study design was used by ANOVA results indicated that there were signifi- evaluating the patients’ transperineal ultrasound cant differences on levator hiatal area among nul- results. This study used consecutive sampling liparous, primiparous, and multiparous women at method with a total of 69 patients. We recruited rest (p=0.012). the women coming to Obstetrics and Gynecology Clinic Dr. Cipto Mangunskusumo hospital from May to December 2015. We exclude the pregnancy Table 3. Comparisons of Levator Hiatal Dimensions women, women with history of pelvic malignancy, Measured at Rest history of pelvic reconstructive surgery, history of NMean (SD) p value pelvic trauma, and inability to contract pelvic floor Nulliparous group 23 10.00 (2.17) 0.028 muscles correctly. We described the characteristics demography of women and analyzed using one Primiparous group 23 10.70 (2.26) way ANOVA to compare the levator hiatal Multiparous group 23 11.96 (2.86) dimension among the groups of women during Valsalva maneuver and at rest. We analyzed the Of 46 primiparous and multiparous women, data using SPSS. there was 1 (2.2%) patient who developed into levator avulsions. No avulsions were observed in RESULTS nulliparous women. Of the 69 patients assessed, there were 23 women in each group of nulliparous, primiparous, and DISCUSSION multiparous. Demographic characteristics of the Levator ani muscle avulsion is common problem in patients were presented in Table 1. women after vaginal delivery and it is likely to be Levator hiatal dimension measured at Valsalva an etiological factor in the development of female maneuver was presented in Table 2. The data dis- POP, especially cystocele and uterine prolapse.1

Table 1. Demographic Characteristics of the Patients Nulliparous (mean (SD)) Primiparous (mean (SD)) Multiparous (mean (SD)) Characteristics Age (years) 31.4 (3.2) 27.0 (21.0 - 42.0)* 46.3 (9.5) Highest birth weight (kg) - 2.9 (0.6) 3.1 (0.4) Body mass index (kg/m2) 23.2 (3.1) 22.8 (3.2) 26.1 (3.7) *Median (min-max) Indones J 210 Juniarto and Moegni Obstet Gynecol Acute levator ani muscle injury can be diagnosed anal canal.6 The second factor affecting the levator clinically through visualization and digital exami- ani muscle during gestation is the constantly nation; whereas, levator avulsion is associated with increasing intraabdominal pressure induced by the large vaginal tear.2 Chronic detachment of the enlarging gravid uterus.7 Previous studies had levator ani muscle from the inferior ramus of pubic stated that the main brunt of the increased intra- bone can be evaluated by palpation.3 abdominal pressure fell on the levator plate, par- The incidence of levator ani muscle avulsion ticularly on the rectococcygeal raphe, which is the following vaginal delivery in our study was around most dependent and durable part of the levator 2.2% and it could be found in primiparous or mul- plate.8-10 Being tendinous, the rectococcygeal tiparous women. Previous studies had shown raphe and hiatal ligament become overstretched higher incidence rate of levator ani muscle and subluxated. The third factor concerning the avulsion, namely 36%4 and 21%5. The very low effect of the gravid uterus on the functional activity incidence rate in our study might be occurred of the levator ani muscle is the mechanical factor. because we only reported major levator ani muscle During last month of pregnancy, the gravid uterus avulsion; meanwhile, the minor levator ani muscle mechanically blocks contraction power of the leva- avulsion was not counted in. tor ani muscle, leading to interfered contraction 6 It is estimated that levator ani muscle injury process. happens not only during delivery but also during According to previous study conducted by the period of pregnancy. During gestation, the Garcia-Mejido11, the most important risk factor gravid uterus enlarges progressively, inducing its associated with avulsion during vaginal delivery is effect on the levator ani muscle, probably through fetal weight. Some studies had shown that birth three mechanisms. The mechanisms are an incre- weight is a risk factor for pelvic floor damage12 and ment of the uterine weight, an elevation of the in- urogenital prolapse.13 However, some studies con- traabdominal pressure, and a mechanical interfer- cluded contrasting results.14-17 Avulsion leads to an ence with its functional activity. Continuously, the enlargement of the levator hiatus, particularly in uterine weight increases during gestation, reaching its anterior part, which is clearly associated with its maximum weight during several final weeks of POP.20 It has been considered that older age is a gestation. The levator ani muscle has to bear this risk factor for avulsion.18-22 weight. At the expense of the levator plate size, the enlarging uterus widens the levator hiatal area Avulsion occurs more frequently in multiparous progressively. The levator hiatus occupies the an- compared with nulliparous women due to greater terior part of the levator plate. The lowest part of contractibility. Zanetti, et al.23 found greater disten- the enlarging uterus engages through the levator sibility in the multiparous than in the nulliparous hiatus, resulting progressive widening of the hia- women (20.07 (SD 0.46) cm vs 19.3 (SD 2.8) cm; tus. Meanwhile, the uterus encroaches on the leva- p<0.001) during delivery. In addition, previous tor plate, reducing to the minimum its transverse study conducted by Petricelli, et al.24 suggested diameter across the pelvic cavity. As a result, the that nulliparous women had higher electrical levator plate sags down, leading to suspensory activity compared to multiparous women. The sling subluxation in addition to widening and mechanical and hormonal effects of pregnancy may lowering of the levator hiatus. Hence, most of the induce biomechanical, neurological or neuromus- anal canal, urethra, and vagina lie above and they cular changes to the pelvic floor and pelvic organ are exposed to the direct effect of the intraabdo- supports25,26 and they may contribute to pelvic minal pressure. The lowered and widened levator floor dysfunction, independently of delivery mode. hiatus exposes anal canal and urethra directly to Weidner, et al.27 had demonstrated that pregnancy the intra abdominal pressure on straining at had negative effect on the electromyographic defecation or urination. Then, it is transmitted activity of the urethral rhabdo sphincter. through the abnormally wide levator hiatus to the anal canal and urethra leading to their obstruction. The limitation of this study included small It is predicted that the high anal canal pressure sample size. The prevalence of avulsion in this recorded during levator ani muscle contraction on study was very low (2.2%); while, the differences straining in multiparous women coming from the between nulliparous and multiparous group could increased intra abdominal pressure directly to the not be observed any further. Vol 4, No 4 October 2016 Comparison of the levator hiatal area 211 CONCLUSION 14. Albrich SB, Laterza RM, Skala C, et al. Impact of mode of delivery on levator morphology: a prospective observa- It is essential to perform the measurement of the tional study with three-dimensional ultrasound early in the levator hiatus in pregnant women. By measuring postpartum period. BJOG. 2012; 119: 51-60. the levator hiatus, the incidence of POP could be 15. Shek K, Dietz HP. Intrapartum risk factors for levator predicted; therefore, preventive management can trauma. BJOG. 2010; 117: 1485-92. be held earlier during the process of delivery. 16. Chan SS, Cheung RY, Tui AK, et al. Prevalence of levator ani muscle injury in Chinese women after first delivery. Ultra- sound Obstet Gynecol. 2012; 39: 704-9. REFERENCES 17. Cassado J, Pessarradona A, Espun AM, et al. Four-dimen- sional sonographic evaluation of avulsion of the levator ani 1. Dietz HP, Bhalla R, Chantasorn V, Shek KL. Avulsion of the according to delivery mode. Ultrasound Obstet Gynecol. puborectalis muscle is associated with asymmetry of the 2011; 38: 701-6. levator hiatus. Ultrasound Obstet Gynecol 2011; 37(6): 723- 6. 18. Kearney R, Miller JM, Ashton-Miller JA, DeLancey JO. Obs- tetric factors associated with levator ani muscle injury after 2.Dietz HP, Gillespie AV, Phadke P. Avulsion of the pubovis- vaginal birth. Obstet Gynecol. 2006; 107: 144-9. ceral muscle associated with large vaginal tear after normal vaginal delivery at term. Aus N Z J Obstet Gynaecol 2007; 19. Dietz HP, Simpson JM. Does delayed child-bearing increase 47: 341-4. the risk of levator injury in labour? Aus N Z J Obstet Gynecol. 3. Schwertner-Tiepelmann N, Thakar R, Sultan AH, Tunn R. 2007; 47: 491-5. Obstetric levator ani muscle injuries: current status. Ultra- 20. Ecker J, Chen K, Cohen A, et al. Increased risk of cesarean sound Obstet Gynecol, 2012; 39: 372-83. delivery with advancing maternal age: indications and as- 4. Dietz HP, Lanzarone V. Levator trauma after vaginal deli- sociated factors in nulliparous women. Am J Obstet Gynecol. very. Obstet Gynecol 2005; 106: 707-12. 2001; 185: 883-7. 5. van Delft K, Thakar R, Sultan AH, et al. Levator ani muscle 21. Bell JS, Campbell DM, Graham WJ, et al. Can obstetric com- avulsion during childbirth: a risk prediction model. BJOG. plications explain the high levels of obstetric interventions 2014; 121: 1155-63. and maternity service use among older women? A retro- 6.Shafik A, El-Sibai O. Study of the levator ani muscle in the spective analysis of routinely collected data. BJOG. 2001; multipara. J Obstet Gynaecol. 2002; 22(2): 187-92. 108: 910-8 7. Shafik A. A new concept of the anatomy of the anal 22. Marsoosi V, Jamal A, Eslamian L, Oveisi S, Abotorabi S. Pro- sphincter mechanism and the physiology of defecation. longed second stage of labor and levator ani muscle injuries. Mass contraction of the pelvic floor muscles. International Glob J Health Sci. 2015; 7(1): 267-73. Urogynecol J. 1998; 9: 28-32. 23. MR Zanetti, Avalia ca oquantitativa da extensibilida de 8. Shafik A. A new concept of the anatomy of the anal perineal em parturientes [Ph.D. thesis], Departamento de sphincter mechanism and the physiology of defecation. II. Obstet cia, Universidade Federal de Sao Paulo, 2010. Anatomy of the levator ani muscle with special reference to puborectalis. Invest Urol. 1975; 13: 175-82. 24. Petricelli CD, Resende AP, Elito Júnior J, et al. Distensibility and strength of the pelvic floor muscles of women in the 9. Shafik A. A new concept of the anatomy of the anal third trimester of pregnancy. Biomed Res Int. 2013; sphincter mechanism and the physiology of defecation. VIII. Levator hiatus and tunnel. Anatomy and function. Diseases 437867-10. of the Colon and Rectum. 1979; 22: 539-49. 25. South MMT, Stinnett SS, Sanders DB, Weidner AC. Levator 10. Shafik A. Constipation: some provocative thoughts. J Clin ani denervation and reinnervation 6 months after child- Gastroenterol. 1991; 13: 259-67. birth. Am J Obstet Gynecol. 2009(5); 519: e1-519.e7 11. Falkert A, Endress E, Weigl M, Seelbach-Go? bel B. Three- 26. Chen B, Wen Y, Yu X, Polan ML Elastin metabolism in pelvic dimensional ultrasound of the pelvic floor 2 days after first tissues: is it modulated by reproductive hormones? Am J delivery: influence of constitutional and obstetric factors. Obstet Gynecol. 2005; 192: 1605-13 Ultrasound Obstet Gynecol. 2010; 35: 583-8. 27.Hunskaar S, Arnold EP, Burgio K, Diokno AC, Herzog AR, 12. Snooks SJ, Swash M, Henry MM, Setchell M. Risk factors in Mallett VT (2000) Epidemiology and natural history of uri- childbirth causing damage to the pelvic floor innervation. nary incontinence. [Review] [161 refs]. Int Urogynecol J. Int J Colorectal Dis. 1986; 1: 20-4. 2000; 11(5): 301-19. 13. Chiaffarino F, Chatenoud L, Dindelli M, Meschia M, Buonaguidi A, Amicarelli F, et al. Reproductive factors, family history, occupation and risk of urogenital prolapse. Eur J Obstet Gynecol Reprod Biol 1999; 82: 63-7. Indones J 212 Djusad et al Obstet Gynecol

Research Article

Characteristics of Patients with Obstetric and Gynecologic Fistula in Jakarta Karakteristik Pasien dengan Fistula Obstetri dan Ginekologi di Jakarta

Suskhan Djusad, Ambalagen Sonia, Anthonyus Natanael Department of Obstetrics and Gynecology Faculty of Medicine Universitas Indonesia/ Dr. Cipto Mangunkusumo Hospital Jakarta

Abstract Abstrak

Objective: To know the characteristics of patients with obstetrics Tujuan: Diketahuinya karakteristik pasien dengan fistula obstetri dan and gynecologic fistula in Dr. Cipto Mangunkusumo Hospital, ginekologi di RSCM, Jakarta. Jakarta. Metode: Studi ini merupakan studi deskriptif dengan menggunakan Method: This study was a descriptive design using secondary data data sekunder dari rekam medis dan data rekapitulasi pada tahun from medical records and patient database during 2011-2016. 2011-2016. Result: There were 68 subjects with fistula. From 2011-2016, there Hasil: Terdapat total 68 subjek yang didiagnosis dengan fistula. Dari were 5 cases (7.4%), 19 cases (27.9%), 16 cases (23.5%), 11 cases tahun 2011 - 2016, terdapat 5 kasus (7,4%), 19 kasus (27,9%), 16 (16.2%), 8 cases (11.8%), and 9 cases (13.2%) of fistula; respec- kasus (23,5%), 11 kasus (16,2%), 8 kasus (11,8%), dan 9 kasus tively. The average age of subjects was 38 years old and only 34 (13,2%), berurutan. Usia rata-rata subjek adalah 38 tahun dan hanya subjects have complete data. Gynecologic and obstetric fistula were 34 subjek yang memiliki data yang lengkap. Fistula ginekologi dan 17 cases each. As total 28% of fistula cases were vesicovagina fistula, obstetri masing-masing sebanyak 17 kasus. Fistula vesikovagina 12% were rectovaginal fistula, 9% were anovagina fistula, and the sebanyak 28%, fistula rektovagina sebanyak 12%, fistula anovagina other types of fistula were 2%. Among 34 subjects, there were 21% sebanyak 9%, dan fistula tipe lain sebanyak 2%. Dari 34 subjek, of vesicovagina fistula and 3% of rectovagina fistula, which were didapatkan fistula vesikovagina (21%) dan rektovagina (3%) yang caused by iatrogenic. There were 7% of vesicovagina and recto- disebabkan oleh tindakan iatrogenik. Fistula vesikovagina dan vagina fistula each and 9% of anovagina fistula were caused by rektovagina masing-masing sebanyak (7%) dan anovagina (3%) obstetric problems. The iatrogenic procedures found from this study disebabkan oleh masalah obstetri. Tindakan iatrogenik yang didapat were total abdominal hysterectomy (16%), vaginal hysterectomy pada studi ini adalah histerektomi total abdominal (16%), histe- (3%), and neovagina (3%). rektomi transvaginal (3%), dan neovagina (3%). Conclusion: The trend of cases is decreasing during the present Kesimpulan: Tren jumlah kasus menurun pada saat tahun 2011 - years (2011-2016). Gynecologic fistula cases caused by iatrogenic 2016. Fistula ginekologi yang disebabkan oleh tindakan iatrogenik are the major problems, but the obstetrics fistula cases decreasing merupakan masalah utama saat ini dibandingkan dengan jumlah following the labor monitoring is much better nowadays. kasus fistula obstetri yang menurun seiring pemantauan persalinan yang lebih baik. [Indones J Obstet Gynecol 2016; 4-4: 212-217] [Maj Obstet Ginekol Indones 2016; 4-4: 212-217] Keywords: gynecologic fistula, iatrogenic, obstetric fistula Kata kunci: fistula ginekologi, fistula obstetri, iatrogenik

Correspondence: A. Sonia, [email protected]

INTRODUCTION nutrition, sexual dysfunction, and the disturbance of mental health (anxiety and depression), insom- In developing countries, fistula is the conseqence nia, and attempt of suicides.1 of poor perinatal care. Fistula can be found per 1,000 labors and the prevalence of fistula is around A study conducted by Waaldjik in Africa showed 0.1% to 1.5% per 1000 pregnancies. The major risk that the incidence of fistula was 1-2 cases per 1,000 factors are early marriage, short stature, poor an- deliveries. The number of incidence represented tenatal care, low socio-economic status, low edu- 50,000-100,000 new cases and the prevalence of cational level, and family income or occupation.1 fistula could reach 2 million of cases in the world However, the main factor causing obstetric fistula nowadays. In Zambia, there were 259 cases of is obstructed labor. Female who gets fistula will af- obstetric fistula, but there were only 95.5% cases fect their psychosocial status. The psychosocial of obstetric fistula reported as the consequences of condition, as mentioned, are divorces (16-92%), prolonged labor (more than 24 hours). In Ethiopia, socially isolated, the deterioration of poverty, mal- around 92% cases of obstetric fistula were related Vol 4, No 4 October 2016 Characteristics of patients with obgyn fistula 213 to poor antenatal care. In Nigeria, there were 85% RESULTS cases of fistula caused by labored at home.1 The data was obtained during the last 5 years and Based on a study, there were 8.9% to 86% pa- the results were 68 subjects who were diagnosed tients with obstetric fistula who were found mostly with fistula. Of 68 subjects, there were 28% in teenagers. Besides, around 31% to 66.7% of patients of vesicovagina fistula, 11% patients of cases were found in primiparous women. The mean rectovagina fistula, 9% patients of anovagina fis- time of labor which increased the risk of fistula tula, and 2% patients with other types of fistula was from 2.5 to 4 days. About 20% to 95.7% of (urethrovagina, vesicocervicovagina, vesicorecto- women getting the obstetric fistula had pro- vagina). These number were the summary of both longed labor (more than 24 hours).2 obstetric and gynecologic fistula. The average age In developing countries, as well as industrial of the subjects was 38 years old. countries, the prevalence of gynecologic fistula is In this study, there were 3 subjects under 20 still lowered as compared with obstetric fistula.1 years old, 29 subjects who were 20 to 35 years old, In developing countries, there are more than 90% and 36 subjects who were above 35 years old. of urogenital fistula caused by pelvic surgery. The Meanwhile, the distribution of nulliparous, primi- involvement of urinary tracts is around 1% of gyne- parous, and multiparous women were 4, 13, and cologic surgery and caesarean section.3 There-fore, this study aims to know the characteristics of pa- 15 subjects; contributively. tients with obstetric and gynecologic fistula in Dr. The cases of obstetric fistula had several risk Cipto Mangunkusumo Hospital. factors including the heaviest birth weight and the degree of obstetrical anal sphincter injuries (OA- SIS). In this study, there were only 1 subject with METHODS history of having labor less than 2,500 grams, 19 subjects of 2,500-4,000 grams, and 3 subjects of This was a descriptive study design. We recruited above 4,000 grams. Based on the degree of perineal samples from secondary data of medical records laceration, there were no subjects who had mild and patient databases in Division of Urogyneco- degree of perineal laceration (1st degree and 2nd logy, Department of Obstetrics and Gynecology, Fac- degree of perineal rupture); however, there were ulty of Medicine Universitas Indonesia, Dr. Cipto 12 subjects who had severe perineal laceration Mangunkusumo Hospital, between 2011 and 2016. (>2nd degree). The inclusion criteria were women diag-nosed with fistula during the period of time. The types of fistula Based on the types of fistula, there were vesi- were categorized into obstetric and gynecologic fis- covagina, rectovagina fistula, anovagina, and other tula. Each of them would be divided into vesico- types including urethrovagina, vesicocervicovagi- vagina, rectovagina, anovagina, and the other types na, and vesicorectovagina fistula. Among 68 sub- of fistula. In the age category, it would be divided into 3 groups, such as under 20 years old, 20-35 years old, and above 35 years old. Perineal laceration would be classified into 2 groups, as mild and severe degree of laceration. Mild degree was defined as first and second degree of perineal laceration. Severe laceration was defined as more than second degree of perineal laceration. The heaviest birth weight of newborn would be categorized into 3 groups, namely less than 2,500 grams (small), 2,500-4,000 grams (normal), and more than 4,000 grams (large). The risk factor of obstetric fistula would be seen from the procedure and the problem found in this study. It was similar definition for the gynecologic fistula. In this study, all data were processed using SPPS program ver- Figure 1. The Trend of Fistula Cases during 2011-2016 sion 23.0. in Dr. Cipto Mangunkusumo Hospital. Indones J 214 Djusad et al Obstet Gynecol jects, there were 35 subjects diagnosed as vesico- assisted vaginal delivery). In this study, among 34 vagina fistula, 17 subjects as rectovaginal fistula, subjects with complete medical records, there 10 subjects as anovagina fistula, and 6 subjects as were 17 subjects of each case group. From 2011 other types of fistula. to 2016, there were 5 (7.4%), 19 (27.9%), Fistula is classified as two types, such as obste- 16 (23.5%), 11 (16.2%), 8 (11.8%), and tric and gynecologic fistula. Obstetric fistula is a 9 cases; respectively. Actually, the cases in 2006 fistula caused by obstetric related problems, such were less than other years due to the number of as prolonged second stage of labor, perineal lace- months from samples taken, namely between ration, obstetric procedure (caesarean section and January and March.

Table 1. The Characteristics of Obstetric and Gynecologic Fistula in Dr. Cipto Mangunkusumo Hospital during 2011 to 2016 N = 68 (%) Variables Obstetric fistula Gynecologic fistula n (%) n (%) Age < 20 years old 1 (2) 0 (0) 20 - 35 years old 13 (19) 3 (4) > 35 years old 3 (4) 14 (21) N/A 34 (50) The types of fistula Vesicovagina 5 (7) 14 (21) Rectovagina 5 (7) 3 (4) Anovagina 6 (9) 0 (0) Others 1 (2) 0 (0) N/A 34 (50) Risk Factors For obstetric Caesarean section 3 (4) Prolonged second stage of labor 1 (2) Assissted/operative vaginal delivery 2 (3) Perineal laceration Mild 0 (0) Severe 12 (18) The heaviest birth weight of newborn Small (< 2500 grams) 1 (2) Normal (2500-4000 grams) 13 (19) Large (> 4000 grams) 3 (4) Gynecologic procedures/abnormalities Transvaginal hysterectomy (TVH) 2 (3) Total abdomninal hysterectomy (TAH) 11 (16) Neovagina 2 (3) Pelvic organ prolapse 2 (3) Sexual abused 0 (0) N/A 34 (50) Vol 4, No 4 October 2016 Characteristics of patients with obgyn fistula 215 Among the subjects who had obstetric fistula study conducted by Kazaura, et al., they stated that mostly were in the range of 20 years old until 35 there were 334 subjects who had obstetric fistula, years old. However, there was one subject who had 72.2% among them were in the range of 25-29 obstetric fistula in the age of under 20 years old. years old.4 One meta-analysis study conducted by The type of fistula mostly was anovagina fistula, Ahmed, et al. showed that almost 80% of women which were found around 6 cases. Meanwhile, had chronic excoriation due to direct irritation by vesicovagina and rectovagina fistula were as many urine.4 as the other types of fistula namely 5 cases. Fistula tended to interfere women’s social and One of risk factors is obstructed labor. In this psychosexual life. In a study conducted by Okoyei, study, there was one subject who had obstetric et al., women who had fistula had been in emo- fistula because of prolonged second stage of labor. tional instability.4 However, in this study, we did In addition, assisted vaginal delivery including not do assessment of psychosexual aspects among forceps and vacuum, influenced the fistula forma- the subjects. tion. This study reported that there were 2 subjects who had obstetric fistula with a previous history Especially, obstetric fistula is caused by obstruc- 5 of assisted vaginal delivery. ted labor which happened during full bladder. Early marriage is one of the significant risk factors There were 12 subjects with the previous for the obstetric fistula. Delayed to get married and history of severe perineal laceration. In this study, pregnant will reduce the complications of labor. subjects who had severe perineal laceration, mostly had anovagina and rectovagina fistula. In this study, there were 17 cases of obstetric fistula, caused by prolonged second stage of labor Based on the heaviest birth weight, this study and assissted vaginal delivery (forceps or vacuum). showed that the most cases were found among the There were several primary risk factors, such as subjects having history of delivering 2,500 to 4,000 the duration of labor, the facilities and the health grams. Nevertheless, birth weight more than 4000 workers, partograph, poor antenatal care, early grams affected the fistula formation showed by 3 marriage, and aging population. A study conducted cases in this study. by Unfer, et al. showed that there was higher Most of the gynecologic fistula cases were found incidence of obstetric fistula among women deli- in the age of above 35 years old. Vesicovagina vering low birth weight baby, especially in teenage fistula was the most often types of fistula in this population. The increasing obstetric risk in teenage study. Gynecologic fistula was mostly affected by is due to immaturity of anatomical structure on gynecologic procedure or iatrogenic. In this study, pelvic organ and bone.2 we found several gynecologic procedures, such as The teenage pregnancy has the highest preva- transvaginal hysterectomy, transabdominal hyste- lence in developing countries (7-30%) and it is rectomy, and artificial vagina procedure or neova- associated with the incidence of cephalopelvic dis- gina. There were 2 cases due to transvaginal hys- proportion.6 One of the strategies to reduce obs- terectomy, 11 cases due to transabdominal hyste- tetric fistula is through prevention of teenage preg- rectomy, and 2 cases because of artificial vagina nancy. Women who have height under 155 cm and procedures. There were some gynecologic abnor- the age under 19 years old have 4.9 times higher malities found in this study. They were uterine pro- risk in caesarean section.6 Regardless, caesarean lapse and cystorectocele. This study found 2 sub- jects who had those gynecologic abnormalities. section will increase the maternal and fetal out- 6 Sexual abuse could be one of the risk factors or the comes in obstructed labor. cause of gynecologic fistula called as traumatic The obstructed labor has been the major cause gynecologic fistula. However, this study did not of maternal morbidity, such as infection and obs- find any subjects with the history of sexual abuse. tetric fistula. The obstructed labor is a mechanical process affected by the fetal size and malpresenta- DISCUSSION tion. According to World Health Organization (WHO), prolonged labor is defined as the labor In this study, the average age of the subjects was taking place more than 18 hours. The formation of 38 years old which the most subjects were in the fistula is commonly found among primigravid range of 20-35 years old. This corresponded to a patients. A case study conducted in Addis Ababa, Indones J 216 Djusad et al Obstet Gynecol Africa, there were 97% of vesicovagina fistula study reported that the prevalence of vesicovagina caused by obstructed labor, whereas 65% occurred fistula caused by iatrogenic procedures was 60 to among subjects in the age of under 25 years old, 75% by hysterectomy in non malignant cases, 30% and 63% were primigravid.7 This was different by hysterectomy in malignant cases, and 6% by from our study, which the proportion of fistula is caesarean section.11 The risk of fistula formation of commoner in multiparous than primiparous the pelvic organ associated with hysterectomy was women. Vesicovagina fistula or obstetric fistula is 0.1% to 4%. In a retrospective study in USA, they caused by ischemic necrosis process of bladder tis- showed that gynecologic fistula caused by sue and vagina, which are trapped between the gynecologic procedure was 82%, 8% due to the head of the fetus and the symphisis of maternal obstetric procedure, and also 6% because of during the obstructed labor. Actually, it can impact radiation.11 The incidence of genitourinary fistula to rectovagina fistula, in spite of very rarely condi- caused by abdominal hysterectomy in non malig- tion.7 In case series conducted by Kano, in Sub-Sa- nant cases was 1 from 1,000 cases. The degree of haran Africa, there were 120 subjects who had bladder injury is the main factor of the fistula been diagnosed as vesicovagina fistula and most of formation.11 In a study, where there were 1,317 them had early marriage. In Sokoto, same case se- cases of hysterectomy in non malignant subjects, ries, there were 93.6% of the subjects having mar- there were 46% abdominal hysterectomy, 48% riage before 18 years old. Obstetric fistula was vaginal hysterectomy, and 6% of them were per- mostly found in the age of 20 to 29 years old. formed by laparoscopy. All of them had become the Primiparous was the major group who had been risk factor of vesicovagina fistula followed by in- 8 diagnosed as vesicovagina fistula. traoperative injury of the bladder.11

The most common cause of non obstetric fistula Abdominal hysterectomy in non malignant cases or gyencologic fistula is iatrogenic procedure, such was the second commonest cause (21.6%) of gyne- as pelvic surgery, trauma of the genital (coitus, cologic fistula, while vaginal hysterectomy, radical sexual abused, accident, and genital mutilation), hysterectomy, and laparoscopic hysterectomy granulomatous infection, tuberculosis, and HIV. were 10.8%, 5.4%, and 2.7%, respectively.12 Not only those, but also there are congenital mal- Laparoscopic hysterectomy has the highest formation, cancer especially cervical cancer with or incidence in bladder injury. However, in this study, without radiotherapy which influence to the occur- abdominal hysterectomy has the largest propor- rence of this fistula.9 In this study, among the 34 tion of cases than vaginal hysterectomy. In addi- subjects, there were no subjects with the history tion, there was one case of gynecologic fistula of infection as well as cancer. caused by hysterectomy followed by salphingec- The gynecologic procedures in this study were tomy, as the underlying problem was ovarian cyst. total vaginal hysterectomy, total abdominal This study also found that there were 3 cases of hysterectomy, and artificial vagina or neovagina. fistula with the previous history of caesarean Abdominal hysterectomy surgery has the higher section. Caesarean section has not been the direct risk than vaginal hysterectomy in the formation of cause of the fistula formation but the indication of fistula. However, we did not find the incidence of this procedure should be considered. Indication of fistula in supracervical hysterectomy. Meanwhile, caesarean section could be due to fetal distress and gynecologic abnormalities of genital, such as obstructed labor itself which will be related to uterine prolapse, were rarely found to be the cause obstetric fistula. However, there are several cae- of fistula. Nevertheless, if there are gynecologic sarean section procedures which can be the main abnormalities, they are usually associated with cause of the fistula formation because either there trauma, such as erosion caused by inserting is prolonged and directed pressure on the bladder pessary around vaginal wall near bladder. during the procedure or imperfect closing of the Iatrogenic urogenital fistula can be the result of wound. pelvic surgery and radiotherapy which are associated with tissue damage.10 The strength of this study is the data which were obtained more than 5 years. Especially, this will be The most common type of iatrogenic fistula is enough to represent the prevalence and incidence vesicovagina fistula seen in our study. There were of fistula in Dr. Cipto Mangunkusumo Hospital. This 14 cases out of 17 cases of vesicovagina fistula. A study can be as the reference of the other studies. Vol 4, No 4 October 2016 Characteristics of patients with obgyn fistula 217 The limitation of this study is that there were some 3. Goh J, Stanford EJ, Genadry R. Classification of female incomplete data regarding the subjects. genito-urinary tract fistula: a comprehensive review. Int Urogynecol J Pelvic Floor Dysfunct. 2009; 20(5): 605-10. 4.Service GH. Report on the burden of obstetric fistula in CONCLUSION Ghana. In: Service GH, editor. Ghana: Ghana Health Service; 2015. The number of fistula cases are similar among 5. Neilson J. Obstructed labour. Bri Med Bull. 2003; 67(1): obstetric and gynecologic fistula during 5 years. 191-204. The trend of these cases is decreasing concomitant 6. Rochat CH. Obstetric fistula. Geneva: World Health Organi- to the improvement of technology and surgeon’s zation, Research MEa; 2014. skill. In this study, obstetric fistula cases are caused 7. Kalembo FW, Zgambo M . Obstetric fistula a hidden public by prolonged second stage of labor, operative or health problem In Sub-Saharan Africa. Arts Soc Scienc J. 2012: 9. assisted vaginal delivery, and severe degree of peri- 8.Ijaiya AGR MA, Aboyeji AP, Olatinwo WO, Esuga SA, Ogah neal laceration. Although, gynecologic fistula cases OK, et al. Vesicovaginal fistula a review of Nigerian expe- are mostly caused by hysterectomy or iatrogenic rience. West African J Med. 2010: 29. procedures and they still become the major pro- 9. Dangal G TK, Yangzom K, Karki A. Obstetric fistula in the blem nowadays. Nevertheless, obstetric fistula developing world an agonising tragedy. NJOG. 2013; 8: 11. cases are decreasing in accordance with good labor 10. Raassen TJ, Ngongo CJ, Mahendeka MM. Iatrogenic genitou- monitoring. rinary fistula: an 18-year retrospective review of 805 inju- ries. Int Urogynecol J. 2014; 25(12): 1699-706. 11. Wall LL. Obstetric vesicovaginal fistula as an international REFERENCES public-health problem. The Lancet. 2006; 368(9542): 1201- 9. 1. Abrams PCL, Khoury S, Wein A. Incontinence: ICAD EAU; 12. Singh OSSG, Mathur RJ .Urogenital fistula in women 5-year 2013. experience at a single center. Urol J. 2010; 7: 35-9. 2.Tebeu PM, Fomulu JN, Khaddaj S, de Bernis L, Delvaux T, Rochat CH. Risk factors for obstetric fistula: a clinical re- view. Int Urogynecol J. 2012; 23(4): 387-94. Indones J 218 Arafah et al Obstet Gynecol

Research Article

Perineal Massage during Second Stage of Labor to the Perineal Laceration Degree in Primigravida Efek Masase Perineum Kala Dua Persalinan terhadap Derajat Laserasi Perineum pada Primigravida

Sitti Arafah, David Lotisna, Eddy Tiro Department of Obstetrics and Gynecology Faculty of Medicine Universitas Hasanuddin/ Dr. Wahidin Sudiro Husodo Hospital Makassar

Abstract Abstrak

Objective: To determine the effect of perineal massage during Tujuan: Untuk mengetahui efek masase perineum pada kala II per- second stage of labor on the perineal laceration degree in primi- salinan terhadap derajat laserasi perineum pada primigravida. gravida. Metode: Penelitian ini menggunakan desain uji coba terkontrol tidak Methods: The design of this study was non randomized controlled acak. Dilakukan pelatihan masase perineum terhadap 20 orang trial by conducting massage training of the perineum to 20 obste- residen obstetri dan ginekologi (semua residen telah mengikuti trics and gynecology residents. All residents had passed the normal pelatihan Asuhan Persalinan Normal). Primigravida yang memenuhi delivery care training. Primigravida who met the inclusion criteria kriteria inklusi diikutsertakan dalam penelitian. Kami melakukan were included in this study. We assessed the degree of perineal la- penilaian derajat laserasi perineum pada kasus penelitian. Data ceration in this study. Data were analyzed using Chi square test in dianalisis dengan uji Chi square. SPSS. Hasil: Dari 182 sampel, didapatkan 103 sampel untuk kelompok Results: We obtained 103 subjects for massage group and 79 sub- masase dan 79 sampel kelompok kontrol. Terdapat hubungan yang jects for control group. There was a significant association between bermakna antara perlakuan masase perineum dengan keutuhan pe- massage group and the incidence of intact perineum. In the massage rineum. Pada kelompok masase, mayoritas derajat laserasi adalah group, most of perineal lacerations were first degree of laceration laserasi tingkat 1 (52,4%), sedangkan pada kelompok kontrol mayori- (52.4%); whereas, in the control group, most of them were second tas derajat laserasi adalah laserasi tingkat 2 (77,2%). Hasil uji statistik degree of laceration (77.2%). Statistical analysis showed a signifi- menunjukkan hubungan yang bermakna antara masase perineum cant association between perineal massage and decreased of peri- dan penurunan derajat laserasi perineum (p<0,05). neal laceration degree (p<0.05). Conclusion: Perineal massage during second stage of labor in primi- Kesimpulan: Masase perineum kala II persalinan pada primigravida gravida can reduce the degree of perineal laceration. dapat menurunkan derajat laserasi perineum. [Indones J Obstet Gynecol 2016; 4-4: 218-221] [Maj Obstet Ginekol Indones 2016; 4-4: 218-221] Keywords: degree of perineal laceration, perineal massage, primi- Kata kunci: derajat laserasi perineum, kala II persalinan, masase pe- gravida, second stage of labor rineum, primigravida

Correspondence: Sitti Arafah, dr.arafahbuchari @gmail.com

INTRODUCTION Three million vaginal deliveries of women were generally experienced perineal trauma caused by During delivery process, women had risk for pe- spontaneous rupture and episiotomy in the United rineal trauma, especially in the first labor. As many States. Complications occured in perineal trauma as 60% of women have ever experienced perineal include bleeding, hematome, abscess, perineal pain, trauma in vaginal delivery and at least 1,000 fistula, dyspareunia, and alvi incontinence.1,3,4 women require perineal suturing after childbirth. There is strong evidence that episiotomy is in- Birth canal trauma is caused by episiotomy, effective to prevent complications from delivery. spontaneous perineal laceration, forceps trauma, Thacker and Banta in 1983 questioned the benefit extraction vacuum or extraction version.1,2 of routine episiotomy. Since 1860 to 1980, the Study in UK showed that 85% of women who incidence of third and fourth degree of perineal undergo vaginal delivery got perineal trauma and rupture in women without episiotomy was two-third of them had to do perineal suturing. between 0 and 6.4% compared with the women Vol 4, No 4 October 2016 Perineal massage during second stage 219 with episiotomy, including from 0 to 23.9%. Their qualified subjects in appropriate to the criteria. The result did not point out the benefit of episiotomy data were analyzed using Chi square and Krustal- in terms of reducing the incidence of urinary and Wallis test in SPSS. The Chi square analysis was alvi incontinence.1,5 used to determine the difference between perineal status on treatment or control group during second Perineal pain was reported more intense imme- stage of labor. Mean while, Krustal-Wallis test diately after postpartum and continued until two- aimed to assess the difference on perineal lacera- week postpartum in 30% of women; even, 7% of tion degree between study and control group. The women experienced the pain up to three-month result was considered significantly if p less than postpartum. Women delivering vaginally without 0.05. perineal trauma or with perineal trauma had se- veral advantages, such as shorter length of stay, better pelvic floor muscle strength and sexual func- RESULTS tion, also low level of depression and perineal pain. Perineal trauma could also cause discomfort and This study was conducted from August 2014 to pain during sexual intercourse.6,7 February 2015 to determine the effect of perineal massage during second stage of labor to the pe- Perineal massage is one of the ways to increase rineal laceration degree in primigravida. We ob- blood flow, elasticity, and relaxation of the pelvic tained 182 subjects divided into two groups: 103 floor muscles. It can soften the perineal tissue; subjects in massage group and 79 subjects as con- thus, it will open without resistance during child- trol group. birth. Perineal massage is able to reduce the risk of perineal trauma or the need for episiotomy at Table 1 showed the characteristics of the subject primigravida.7 distribution. Both massage and control group con- sist of women under 30 years old (545% VS Study by Geranmayeh and Karacam reported 45.5%). Women with low educational background that the decrease of perineal laceration degree and were 26 cases (53.0%) on massage group and 23 episiotomy rate in primigravida was because of cases (47.0%) were not performed the massage; perineal massage performing in the second stage while, for high educational background, there were of labor. However, a study by Stamp concluded that 77 cases (57.9%) in massage group and 56 cases perineal massage in the second stage did not have (42.1%) in control group. Most of women had significant impact on the degree of perineal lacera- occupation both in massage and without massage tion and perineal pain after delivery.8,9 group. According to income, there were 75 cases Study about perineal massage antepartum on (60.0%) with massage and 50 cases (40.0%) primigravida had been held in Makassar; no without massage in high income group and 28 studies focused on perineal massage in the second cases (49.1%) with massage and 29 cases (50.9%) stage of labor in primigravida, yet. Therefore, this without massage in low income group. Chi square study aims to determine the effect of perineal test concluded that there were not significant massage during second stage of labor to the degree differences in each characteristic of subject of perineal laceration in primigravida. including age, education, occupation, and income.

METHODS Table 1. Characteristics of the Subject We used non-randomized controlled trial study. Characteristics Massage (+) Massage (­) p The study was conducted in several teaching hos- (%) (%) pitals of Obstetrics and Gynecology Department, Age (years old) Faculty of Medicine Universitas Hasanuddin, Ma- kassar from August 2014 to February 2015. We re- < 30 85 (54.5) 71 (45.5) 0.180 cruitted all primigravidas who had delivery in se- > 30 18 (69.2) 8 (30.8) veral teaching hospitals of Obstetrics and Gyneco- Education logy Department, Faculty of Medicine Universitas Low 26 (53.0) 23 (47.0) 0.550 Hasanuddin, Makassar. The subjects who met the High 77 (57.9) 56 (42.1) inclusion criteria were asked for the approval par- ticipation in the informed consent. We assessed the Indones J 220 Arafah et al Obstet Gynecol

Occupation was 16.4%, 77.2%, 1.3%, 0%; contributively. There Yes 84 (54.9) 69 (45.1) 0.290 was an association between perineal massage during second stage of labor and the degree of No 19 (65.5) 10 (34.5) perineal laceration (p<0.001). Income High 75 (60.0) 50 (40.0) 0.170 DISCUSSION Low 28 (49.1) 29 (50.9) *Chi square test The characteristics of subjects showed in terms of age, education, occupation, and income were not Table 2 indicated the result on comparative statistically significant with p more than 0.05. analysis of perineal status between perineal therefore, we considered the subjects between massage and control (without perineal massage) groups were nomogenaus. In Table 2, we got p group. Of Table 2, perineal status on women in value less than 0.05 for the comparison of perineal status between the perineal massage and control perineal massage group remaining intact and group. In Table 3, the comparison degree of peri- laceration was 43 (41.7%) and 60 (58.3%). Pe- neal laceration between the perineal massage and rineal status in control group who kept intact and control group resulted p value less than 0.05. laceration was on 4 women (5.1%) and 75 women Therefore, our result concluded that the perineal (94.9%). Result of chi-square test indicated that massage can reduce the degree of perineal lacera- there was a relationship of perineal massage tion. during second stage labor and perineal status (p<0.001). Massage aims to relieve pain, produce relaxa- tion, and reduce stress caused by the labor pro- Table 3 showed the result on comparative cess.10 In this study, 41.7% perineum remained in- analysis of the perineal laceration degree between tact on the massage group; while, there were only perineal massage and control group. In this study, 5.1% of subjects had intact perineum in control for perineal massage group, the percentage of pe- group. A study by Labrecque stated that of 283 rineal laceration on first, second, third, and fourth primigravida undergoing perineal massage, there grade was 52.4%, 5.8%, 0%, and 0%; respectively. was 24.5% perineum kept intact compared to Meanwhile, in control group, the percentage of la- primigravida who did not get perineum massage ceration on first, second, third, and fourth degree which showed only 15.1%.11

Table 2. Comparative Analysis of Perineal Status between Perineal Massage and Control Group Perineum Intact (+) Perineum Intact (­)Totalp N%N%N Massage (+) 43 41.7 60 58.3 103 <0.001 Massage (-) 4 5.1 75 94.9 79 Total 47 28.8 135 74.2 182 *Chi square test

Table 3. Comparative Analysis of the Degree of Perineal Laceration between Perineal Massage and Control Group Degree of Laceration Total p Intact Level 1 Level 2 Level 3 Level 4N 43 54 6 - - 103 <0.001 Massage (+) 41.7 52.4 5.8 0 0 413611 79 Massage (-) 5.1 16.4 77.2 1.3 0 Total4767671 0182 *Krustal-Wallis test Vol 4, No 4 October 2016 Perineal massage during second stage 221 In this study, for perineal massage group, the 2. Kalichman L. Perineal massage to prevent perineal trauma percentage of perineal laceration on the first, in childbirth. Israel Med Associat J. 2008; 10: 531-3. second, third, and fourth grade was 52.4%, 5.8%, 3. Fahami F, Shokoohi Z, Kianpour M. The effect of perineal management technique on labor complications. Ir J Mid- 0%, and 0%; respectively. Meanwhile, in control wifery Res. 2012; 17: 55-7. group, the percentage of laceration on the first, 4. Karkata K. Perdarahan pascapersalinan. Ilmu Kebidanan second, third, and fourth degree was 16.4%, 77.2%, Sarwono Prawirodihardjo. 2008; 1: 526. 1.3%, 0%; contributively. This result was in appro- 5. Mei-Dan E, Walfisch A, Raz I. Perineal massage during preg- priate to study by Sofian Muhaji in 2002. They ex- nancy: A prospective controlled trial. 2008; 10: 499-500. plained that the perineal massage group tended to 6. Aasheim V, Nilsen A, Lukasse M, et al. Perineal technique have lower degree of perineal laceration, especially during second stage of labor for reducing perineal trauma. on the first grade (96.7%). Study by Geranmayeh The Cochrane Library. 2011; 12: 2-3. and Karacam in 2012 recorded the similar result 7. Albers L, Borders N. Minimizing genital tract trauma and that in the perineal massage group, the patients related pain following spontaneous vaginal birth. Midwifery Womens Health. 2007; 52: 246-7. had more first degree of perineal laceration (42.9%) compared to higher degree of laceration 8. Karacam Z, Ekmen H, Calisir H. The use of perineal massage in the second stage of labor and follow-up postpartum pe- 8,12 during second stage of labor. rineal outcomes. Health Care for Women International. 2012; 33: 697-8. 9. Stamp G, Kruzins G, Crowther C. Perineal massage in labor CONCLUSION AND SUGGESTION and prevention of perineal trauma. Bri Med J. 2001; 322: 1277. In conclusion, perineal massage on the second stage of labor in primigravida can reduce the de- 10. Mander R. Metode pengendalian nyeri bukan farmakologis. Nyeri Persalinan. 2004; 1: 74-95. gree of perineal laceration. Further studies should 11. Labrecque M, Eason E, Marcoux S. Randomized trial of pe- be held to compare the effectiveness of perineal rineal massage during pregnancy: Perineal Symptoms massage on antenatal and during second stage of Three Months After Delivery. Am J Obstet Gynecol. 2000; labor. 182: 76-80. 12. Muhaji S. Latihan masase perineum pada masa antenatal mengurangi derajat ruptur perineum persalinan primipara. REFFERENCES 2002; 1: 45-6.

1.Scott J. Epsiotomy and vaginal trauma. Obstet Gynecol North Am. 2005; 32: 307-21. Indones J 222 Wigin and Andrijono Obstet Gynecol

Research Article

A Simple Ultrasound Examination as Diagnostic Tool for Malignant Ovarian Tumor Pemeriksaan Ultrasonografi Sederhana sebagai Alat Diagnostik Tumor Ovarium Ganas

Christin Wigin, Andrijono Department of Obstetrics and Gynecology Faculty of Medicine Universitas Indonesia/ Dr. Cipto Mangunkusumo Hospital Jakarta

Abstract Abstrak

Objective: To know the diagnostic value of simple ultrasound exa- Tujuan: Mengetahui nilai diagnostik pemeriksaan ultrasonografi se- mination to detect malignant ovarian tumor. derhana dalam menilai keganasan tumor ovarium dibandingkan hasil Method: This study used cross-sectional design in gynecology out- histopatologi pascaoperasi. patient clinic at Dr. Cipto Mangunkusumo Hospital. We recruited the Metode: Penelitian ini merupakan studi potong lintang pada pasien patients with ovarian tumor undergoing surgery between March tumor ovarium di polikinik Ginekologi RSCM Jakarta yang dilakukan and July 2015. Samples were taken using consecutive sampling. operasi pada bulan Maret-Juli 2015. Sampel penelitian diambil dengan Analysis was done using Chi-square test and logistic regression to metode consecutive sampling. Analisis menggunakan uji Chi-square find the relationship between ultrasound morphologic patterns with dan regresi logistik untuk mencari hubungan antara pola morfologi histopathologic findings, where the significant relationship was p ultrasonografi dengan hasil histopatologi di mana terdapat hubungan value less than 0.05. Furthermore, a model derived from logistic re- bermakna apabila nilai p<0,05. Selain itu, dibuat model persamaan gression was made to calculate the probability having ovarian ma- dari regresi logistik untuk menghitung probabilitas. lignancy. Hasil: Terdapat 80 subjek penelitian di mana 58 subjek (72,5%) de- Result: There were 80 subjects which 58 subjects (72.5%) had ngan tumor jinak dan 22 subjek (27,5%) dengan tumor ganas. Hasil benign tumor and 22 subjects (27.5%) had malignant tumor. Ultra- ultrasonografi dengan pola morfologi  2 menunjukkan hasil ganas sound examination result using  2 morphologic patterns gave ma- pada 53,8% subjek dengan nilai diagnostik sensitivitas 100%, spesifi- lignant result in 53.8% subjects with the sensitivity of 100%, speci- sitas 82,8%, nilai duga positif 68,8%, dan nilai duga negatif 100%. ficity of 82.8%, positive predictive value of 68.8%, and negative pre- Pola morfologi yang paling berpengaruh terhadap keganasan tumor dictive value of 100%. The most important patterns were irregular ovarium adalah permukaan dalam dinding kista reguler, multilokular, internal cyst wall, multilocular, presence of papillary projection, and terdapat penonjolan papiler, dan ada bagian padat dalam tumor. presence of solid component. The probability of subject having ova- Probabilitas subjek mendapat tumor ganas apabila memiliki pola rian malignancy with  3 morphologic patterns was more than morfologi  3 adalah lebih dari 88,9%. 88.9%. Conclusion: Simple ultrasound examination can be used to detect Kesimpulan: Pemeriksaan ultrasonografi sederhana dapat diguna- malignant ovarian tumor. kan untuk mendeteksi keganasan tumor ovarium. [Indones J Obstet Gynecol 2016; 4-4: 222-226] [Maj Obstet Ginekol Indones 2016; 4-4: 222-226] Keywords: diagnostic, histopathology, morphology pattern; ovarian Kata kunci: diagnostik, histopatologi, pola morfologi, tumor ovarium, tumor; ultrasonography ultrasonografi

Correspondence: Christin Wigin Hia, [email protected]

INTRODUCTION 4,5 Ovarian cancer is the fourth rank of cancer among cer. Among all gynecology cancers in Indonesia, women in developed country.1 In Indonesia, ova- the death rate of ovarian cancer is around 22.6%. rian cancer is the third most often malignancy in Approximately 42.5% of ovarian cancer patients women after cervical and breast cancer.2 Based on seek treatment when already in stage II-IV. About the recent world’s estimation, there are 204,449 70-80% of advanced stage ovarian cancer has new cases annually, in which it contributes to spread widely and goes through metastasis. Five- 124,860 deaths associated with ovarian cancer.3 year-survival rate of ovarian cancer is 72.8% in Ovarian cancer is considered as a silent killer. Five- stage I, 46.3% in stage II, 17.2% in stage III, and year-survival rate depends on the stage of can- only 4.8% in stage IV.5 Vol 4, No 4 October 2016 Diagnostic tool for malignant ovarian tumor 223 A high mortality rate is due to the difficulty to records in Dr. Cipto Mangunkusumo hospital. Sam- detect the early-stage of ovarian cancer. Therefore, ples were taken using consecutive sampling. The holistic approach need to be done to reduce mor- inclusion criteria were patients suspected ovarian tality. The ovarian cancer can be diagnosed from neoplasm in Dr. Cipto Mangunkusumo Hospital comprehensive history taking by exploring the that undergone operative procedure from March to symptoms, potential risk factors, and family his- July 2015 and those patients had a complete medi- tory.6 According to Olson et al. in 2001,7 the ova- cal record to be further investigated. Simple ultra- rian malignancies does not present specific com- sound morphologic patterns analyzed were bila- plaint and they often misleading with dyspepsia teral symmetry, wall surface, unilocular/multilo- syndrome in primary health care. Furthermore, we cular cyst, presence of solid area, and ascites. These should do the physical examination; however, it simple ultrasound morphologic patterns were has poor sensitivity in diagnosing the ovarian can- compared with the histopathology results post cer around 15-51%.6 surgery. We excluded the patients if the history data from histopathology and ultrasound examina- Ultrasound is the best tool to predict ovarian tion were not complete, post chemotherapy in malignancy with the sensitivity of 80-100%.8 Gal- advanced stage of ovarian cancer, solid ovarian van, et al. concluded that ultrasound examination neoplasm, and dermoid cyst. (sensitivity 98.6%; specificity 94.9%) was better than history taking (sensitivity 79.5%; specificity The collected data were statistically analyzed 96.2%) and pelvic physical examination (sensiti- with SPSS version 21.0. Analysis was done using vity 97.3%; specificity 85.9%).9 In order to screen Chi-square test and logistic regression to find the ovarian malignancy, morphological evaluation was relationship between ultrasound morphologic performed in accordance to study by Galvan, et al.9, patterns and histopathologic findings. We consid- Sassone, et al.10, Ferrazzi, et al.11 International Ova- ered the significant relationship when p value was rium Tumor Analysis (IOTA)12 stated that the cri- less than 0.05. We searched for the specificity, sen- teria to detect the malignant ovarian tumor should sitivity, positive and negative predictive value, be seen from several aspects, such as bilateral sym- positive and negative likelihood ratio, and the ac- metry, wall thickness (thin  3mm, thick > 3mm), curacy. Furthermore, a model derived from logistic wall surface (regular/irregular), septation (thin  regression was made to calculate the probability 3mm, thick > 3mm), papillary projection, solid area having ovarian malignancy. This study has been (not present, present  1x1 cm in internal wall sur- approved by the Committee Ethic of RSCM on No. face), ascites, echogenicity (cystic/solid), acoustic 711/ UN2.F1/ETIK/2015. shadow (present/not present), if Doppler examina- tion is available, neovascularization can be examined with resistance index (<0.41). RESULTS Unfortunately, in Indonesia, ultrasound exami- There were 101 patients diagnosed with ovarian nation has not become a standard procedure in neoplasm and we excluded 21 patients; therefore, primary health care. In primary health care, ultra- the number of subjects analysed in this study were sound examination is usually performed to screen 80 subjects. The mean age of the subjects was 39.1 obstetric problem not in gynecologic problem. In (SD 12.4) years old. The age of malignant group order to reduce mortality rate of ovarian cancer, was older than benign group (44 vs 36 years old). screening is necessary in primary health care. This Forty-five percent of the subjects were nullipara. study aims to evaluate the use of simple ultra- The commonest symptom felt by subjects was sound examination in assessing ovarian tumor in abdominal enlargement (76.3%). The median level Indonesia. In the future, it is expected that ultra- of CA-125 was higher in malignant group com- sound examination can be a routine diagnostic tool pared with benign one (247 U/ml vs 127 U/ml). for ovarian cancer screening in primary health The histopathology results showed that 27.5% care. was malignant with mucinous cystadenocarcinoma (10%) at most. While, of the benign group, en- METHODS dometriosis cyst (35%) was the highest preva- lence. There was significant relationship between This study was descriptive analytic with cross sec- morphologic patterns from ultrasound and his- tional design using secondary data from medical topathology results (p<0,001). If we used  2 ma- Indones J 224 Wigin and Andrijono Obstet Gynecol lignant morphologic patterns found, the sensitivity with the probability of each subject having the 100%, specificity 82.8%, positive predictive value outcome of ovarian malignancy was calculated by: (PPV) 68.8% and negative predictive value (NPV) p = 1/(1 + e(-y)) 100%. Whereas, if we used  3 malignant mor- phologic patterns, the sensitivity, specificity, PPV, NPV were 77.3%, 89.7%, 73.9%, 91.2%; consecu- Table 3. Probability of the Subjects to Become Ovarian Neoplasm Correlated with Type and Number of Morpho- tively. logic pattern There was significant relationship between his- Variable y P topathology results and morphologic patterns of (A) Wall iregularity -3.452 3.1% ultrasound, such as wall irregularity (p<0.001), (B) Multilocular -3.993 1.8% multilocular (p=0.002), papillary projection (C) Papillary projection -3.021 4.6% (p=0.004), presence of solid part (p<0.001), and as- (D) Solid area -3.203 3.9% cites (p=0.008). There was no significant relation- A + B -1.079 2.4% ship between histopathology result and bilateral A + C -0.107 47.3% symmetry (p=0.137) (shown on Table 1). After all A + D -0.289 42.8% the data had been collected, all variables with p B + C -0.648 34.3% value < 0.25 in the bivariate analysis was inserted B + D -0.830 30.4% to multivariate analysis (shown on Table 2). The C + D 0.142 53.5% result explained that morphologic patterns that in- A + B + C 2.266 90.6% fluenced the malignancy together were wall irregu- A + B + D 2.084 88.9% larity, multilocular, papillary projection, and pres- A + C + D 3.056 95.5% ence of solid part. B + C + D 2.515 92.5% A + B + C + D 5.429 99.6%

Table 1. Diagnostic Value of Ultrasound Morphologic Pattern. Diagnostic value Morphologic pattern P Sens Spec PPV NPV LR+ LR­ Accuracy Uni/bilateral 0.137 54.5% 63.8% 36.4% 78.7% 1.51 0.71 61.3% Wall surface <0.001 54.5% 94.8% 80.0% 84.6% 10.55 0.48 83.8% Locus 0.002 63.6% 74.1% 48.3% 84.3% 2.46 0.49 71.3% Papillary projection 0.004 31.8% 94.8% 70.0% 78.6% 6.15 0.72 77.5% Solid area <0.001 90.9% 77.6% 60.6% 95.7% 4.06 0.12 81.3% Ascites 31.8% 31.8% 93.1% 63.6% 78.3% 4.61 0.73 76.3% *Sens = sensitivity *NPV = negative predictive value *Spec = specificity *LR (+) = ikelihood ratio (+) *PPV = positive predictive value *LR (+) = likelihood ratio (-)

Table 2. Multivariate Analysis of Ultrasound Morphologic Table 3 showed that the greatest probability of Pattern and Histopathology Result the morphologic pattern leading to malignancy; Variable p value OR 95% CI while, if it appeared alone, the highest chance of Wall surface 0.010 18.42 2.02 - 167.93 being ovarian neoplasm was papillary projection Locus 0.019 10.73 1.47 - 78.37 Papillary projection 0.011 28.37 2.14 - 375.43 (4.6%) followed by solid area (3.9%). If there were Solid area 0.009 23.64 2.19 - 254.73 2 morphologic patterns, the probability of malig- nancy was ranged from 25.4% to 53.3%. If there were 3 morphologic patterns, the probability of We got the equation model that obtained from multivariate analysis with malignancy was increased between 88.9% and y = -6,366 + 2,914* (Irregular of the wall) + 2,373* 95.5%. If the subjects had 4 morphologic patterns, (multilocular) + 3,345* (presence of papillary pro- the probability was almost perfect (99.6%). jection) + 3,163* (solid area) Vol 4, No 4 October 2016 Diagnostic tool for malignant ovarian tumor 225 DISCUSSION positive predictive value (PPV), and negative pre- dictive value (NPV) were 100%, 82.8, 68.8%, The mean age of the subjects was 39.2 (SD 12.4) 100%; respectively. While finding  3 malignant years old with the age of malignant group was morphologic patterns, the sensitivity, specificity, older than benign group (44 vs 36 years old). The PPV, NPV were 77.3%, 89.7%, 73.9%, 91.2%; res- result was similar to study conducted by Yazbek, pectively. Similar result was obtained in the study et al. in King’s College Hospital, London. The mean by Hafeez S, et al., the sensitivity of ultrasound in of patient’s age with malignancy was 52 years old detecting ovarian malignancy was 93%, specificity and the mean of patient’s age with benign adnexa 89%, positive predictive value 91%, negative pre- 13 tumor was 39 years old. As in literature, the risk dictive value 89% and the accuracy reached 91%.8 of malignancy in ovarian neoplasm was higher as the increasing of age. From bivariate analysis, there was significant re- lationship between histopathology results and The median of labor history was once (0-5 morphologic patterns of ultrasound, such as wall times) with 45% of them were nullipara. Similar to irregularity (p<0.001), multilocular (p=0.002), pa- Goff, et al. study, there were 1,709 subjects; pillary projection (p=0.004), presence of solid part 14 whereas, 48% of them were nullipara. Conti- (p<0.001), and ascites (p=0.008). There was no sig- nuous ovulation associated with nulliparity nificant relationship between histopathology re- increases the risk of ovarian malignancy because sults and bilateral symmetry (p=0.137). All vari- every ovulation cycle will induce invagination and ables with p value < 0.25 in the bivariate analysis damage to the surface of epithelial cell. was inserted into multivariate analysis, in which The commonest symptom was abdominal en- the morphologic pattern that influenced the malig- largement (76.3%) in malignant group (95.5%) nancy were wall irregularity, multilocular, papil- and benign group (69.0%). This result was similar lary projection, and presence of solid part. Similar to Goff, et al. study from 128 women (84 benign result was shown by the study of Timmerman, D tumor and 44 malignant tumor), the most often et al. which found a significant relationship complaint was bloating (70%) followed by abdo- between morphology patterns from ultrasound in minal enlargement (64%).14 Symptom of ovarian ovarian neoplasm, such as ascites, irregularity of neoplasm was not specific; thus, ovarian malig- wall, papillary projections, bilateral symmetry, nancy was difficult to detect in early stage. septum, and acoustic shadow and the results of histopathology (p<0.01). A significant relationship Level of tumor marker CA-125 in malignant tu- was also found in multilocular with solid parts (p mor had a median of 247 U/ml; while, the benign <0.01), unilocular with solid parts (p = 0.02), tumor was 127 U/ml. Similar result obtained in a multilocular and unilocular without solid part (p retrospective study by Bouzari Z, et al. on 182 <0.01), and the presence of the solid part (p women that the level of CA-125 as the tumor <0.01).12 This study found that no significant marker was higher in cases with malignant ovarian relationship in bilateral symmetry pattern, this was tumor than benign. Bouzari, et al. found that the due to many benign tumors in this study had cut-off point of CA-125 (88 U/ml) would offer the bilateral pattern (63.6%). sensitivity of 88%, specificity of 97%, positive predictive value of 84% and negative predictive In this study, the presence of solid part had the value of 99%.15 highest sensitivity (90.9%), while the highest specificity was wall irregularity and papillary pro- The histopathology results described that 27.5% jection (94.8%). The best positive predictive value was malignant with mucinous cystadenocarcinoma was wall irregularity (80%) and the best negative (10%) at most. While from the benign group, en- predictive value was presence of solid part dometriosis cyst (35%) was the most often. This (95.7%). The highest accuracy rate was wall result was not much different from Timmerman D, irregularity (83.8%). The greatest probability of et al. study on 1,066 subjects; 27% of them were the morphologic pattern leading to malignancy malignant.12 while appearing alone was papillary projection There was significant relationship (p<0.001) be- 4.6% followed by presence of solid part 3.9%. If tween morphologic patterns from ultrasound and there were 2 morphologic patterns, the probability histopathology results. If using  2 malignant mor- of malignancy was ranged from 25.4% to 53.3%. If phologic patterns found that sensitivity, specificity, there were 3 morphologic patterns, the probability Indones J 226 Wigin and Andrijono Obstet Gynecol of malignancy was increased between 88.9% and 4.Evans J, Ziebland S, McPherson A. Minimizing delays in 95.5%. If the subjects had 4 morphologic patterns, ovarian cancer diagnosis: an expansion of Andersen’s model the probability was 99.6%. The diagnostic value of of ’total patient delay. Family Practice. 2006; 24(1): 48-55. morphologic pattern in Timmerman D, et al. study 5. Marice S, Sirait A. Angka ketahanan hidup penderita kanker ovarium RS Dr. Cipto Mangunkusumo, Jakarta. Maj Ked In- (1,066 subjects with adnexal tumor), found the dones. 2007; 10: 346-52. highest sensitivity was the presence of solid part 6. RCOG. Management of suspected ovarian masses in pre- (91.8%), while the highest specificity was ascites menopausal women. Green-top Guideline. 2011; 62: 1-14. 12 (96.1%). Factors in Timmerman study correla- 7. Olson S, Mignore L, Nakraseive C, et al. Symptoms of ovarian ting to ovarian malignancy using logistic regresion cancer. Obstet Gynecol. 2001; 98: 212-7. were age, history of ovarian tumor in family (OR 8. Hafeez S, Sufian S, Beg M, et al. Role of ultrasound in char- 4.95), diameter of tumor, diameter of solid part, acterization of ovarian masses. Asian Pasific J Cancer Prev. presence of ascites (OR 4.72), presence of blood 2013; 14(1): 603-6. flow in papilarry projection (OR 3.23), presence of 9. Galvan R, Alcazar J, Royo P, et al. Assessment of an ultra- solid part (OR 2.53), wall iregularity of the cyst (OR sound-based scoring system for triaging ovarian tumors in 3.13).12,16 In study by Timmerman, et al., they in- symptomatic women. Donald School J Ultrasound Obstet Gynecol. 2009; 3(1): 9-14. cluded demographic characteristics and ultrasound result as the malignancy predictor in ovarian neo- 10. Sassone AM, Timor-Tritsch IE, Artner A, et al. Transvaginal sonographic characterization of ovarian disease: evaluation plasm; meanwhile, in this study, we only recruitted of a new scoring system to predict ovarian malignancy. the ultrasound patterns. Based on that, we found Obstet Gynecol. 1991; 78(1): 70-6. similar result where the presence of solid compo- 11. Ferrazzi E, Zanetta G, Dordoni D, et al. Transvaginal ultra- nents and irregular internal wall surface of the cyst sonographic characterization of ovarian masses: compari- tended to malignancy.16 son of five scoring systems in multicenter study. Ultrasound Obstet Gynecol. 1997; 10: 192-7. 12. Timmerman D, Testa A, Bourne T, et al. Simple ultrasound- CONCLUSION based rules for the diagnosis of ovarian cancer. Ultrasound Obstet Gynecol. 2008; 31: 681-90. In order to reduce mortality rate of ovarian cancer, 13. Yazbek J, Raju K, Nagi J, et al. Accuracy of ultrasound sub- screening is necessary in primary health care. jective ’pattern recognition’ for the diagnosis of borderline Simple ultrasound examination is a great diagnos- ovarian tumors. Ultrasound Obstet Gynecol 2007; 29: 489- tic tool which has high sensitivity and specificity in 95. diagnosing ovarian malignancy 14. Goff B, Mandel L, Melancon C, et al. Frequency of symptoms of ovarian cancer in women presenting to primary care clin- ics. JAMA. 2004; 291: 2705-12. REFERENCES 15. Bouzari Z, Yazdani S, Ahmadi M, et al. Comparison of three malignancy risk indices and CA-125 in the preoperative 1.Elmasry K, Gayther S. Epidemiology of ovarian cancer. evaluation of patients with pelvic masses. BMC Research Reznek R, editor. In Cancer of the Ovary: Cambridge Uni- versity Press; 2007: 1-19. Notes. 2011; 4(206): 1-4. 2. Aziz M. Gynecological cancer in Indonesia. Gynecol Oncol. 16. Timmerman D, Testa A, Bourne T, et al. Logistic regression 2009; 20(1): 2. model to distinguish between the benign and malignant adnexal mass before surgery: a multicenter study by the 3. Jhamb N, Lambrou N. Epidemiology and Clinical Presenta- international ovarian tumor analysis group. J Clin Oncol. tion of Ovarian Cancer. Bristow R, Armstrong D, editors. In: Early Diagnosis and Treatment of Ovarian Cancer: Saun- 2005; 23(24): 8794-801. ders Elsevier; 2010: 1-16. Vol 4, No 4 October 2016 Efficacy and safety of cryotherapy in Jakarta 227

Research Article

Efficacy and Safety of Cryotherapy in "See and Treat" Program in Jakarta Primary Health Centre Efektivitas dan Keamanan Krioterapi pada Program See and Treat di Puskesmas Wilayah Jakarta

Linda Lestari, Gatot Purwoto, Laila Nuranna Department of Obstetrics and Gynecology Faculty of Medicine Universitas Indonesia/ Dr. Cipto Mangunkusumo Hospital Jakarta

Abstract Abstrak

Objective: To evaluate the efficacy and safety of cryotherapy in "See Tujuan: Untuk mengevaluasi efektivitas dan keamanan krioterapi and Treat" program in Jakarta Primary Health Care. pada program "See and Treat" di Puskesmas wilayah Jakarta. Method: Using descriptive cross-sectional design, data from medical Metode: Dengan desain deskriptif potong lintang, data dari rekam records were taken with total sampling method. We took the VIA medis diambil dengan metode total sampel. Variabel yang dicatat result, cryotherapy procedure, first-marriage age, number of adalah hasil IVA, tindakan krioterapi, usia pertama menikah, jumlah marriage, parity, smoking habit, and the use of contraception. Data pernikahan, paritas, kebiasaan merokok, dan penggunaan kontra- were analyzed univariately. sepsi. Data dianalisis secara univariat. Result: Of 86 data, the percentage of cryotherapy to change from Hasil: Dari 86 data yang dianalisis, persentase keberhasilan krioterapi positive to negative of VIA result was 90.70%. We did not find the dalam konversi hasil IVA mencapai 90,70%. Kami tidak mendapatkan progressivity to invasive cancer. progresivisitas menjadi kanker invasif. Conclusion: Cryotherapy is effective to manage the cervical pre- Kesimpulan: Krioterapi efektif dan aman dalam mengatasi lesi cancerous lesion in "See and Treat" program. prakanker serviks pada program "See and Treat". [Indones J Obstet Gynecol 2016; 4-4: 227-233] [Maj Obstet Ginekol Indones 2016; 4-4: 227-233] Keywords: cryotherapy, Indonesia, see and treat, visual inspection Kata kunci: Indonesia, inspeksi visual asetat (IVA), krioterapi, see and of acetic acid (VIA) treat

Correspondence: Linda Lestari, [email protected]

INTRODUCTION cancer in developing countries are often diagnosed at advanced stage of diseases so that the 5-year Cervical cancer still becomes the main health prob- survival rate is less than 40%.3 Actually, the lem in the world. World Health Organization disease requires 10-20 years to transform from (WHO) in 2012 stated that this disease ranked the pre-cancer lesions to cancer and whenever it fourth most prevalent cancer among women. reaches the advanced stage, the survival rate drops Approximately 528,000 new cases are detected significantly. Compared with its first stage, the each year, 85% of which are found in developing countries. From those cases, 266,000 cases die, second, third, and fourth stage have an estimated where 9 of 10 death cases occur in developing hazard ratio of 3.09, 18.11, and 53.03; respec- 4,5 countries.1 In 2011, Cancer Registry Council of tively. Pathology Specialist Association in Indonesia Structured screening program for cervical stated that this disease was the second most pre- cancer is responsible for decreasing the incidence valent cancer in women with the incidence rate of and mortality rate of cervical cancer in developed 3,047 (12.27%).2 countries. In United States, the incidence of cervical Cervical cancer has higher rate of incidence in cancer had dropped by 70% for the last 50 developing countries compared with developed years.6 Unfortunately, in the developing countries, ones. Furthermore, patients suffering from cervical the screening is not distributed equally and the Indones J 228 Lestari et al Obstet Gynecol coverage is still low. Only 5% of the population has implemented at the low-resource primary health access to the screening program. Apart from that, care in Indonesia. It aimed to diagnose the cervix the health care service is not comprehensive and precancerous lesion through VIA and treat positive holistic causing the high prevalence of cervical VIA result with cryotherapy in Indonesia. The cancer. This problem also includes of low aware- evaluation of VIA conversion was performed 6 ness of the disease among the population. As the months after cryotherapy. Every patient’s data was population grows, there will be an increase num- written on the medical record. ber of cervical cancer patients.7,8 World Health Organization analyzed that in the Participants developing countries, screening program using Pap smear cannot significantly decrease the incidence We included all women who had positive result of and mortality rate of cervical cancer. Limited VIA, had received the cryotherapy as treatment; budget, low competent resources, and inadequate then they visited to control in 6 months after health care system contribute to the failure of Pap cryotherapy and we could track the complete smear screening in those countries.9 Visual inspec- medical records in primary health care. We catego- tion with acetic acid (VIA) is known as the alterna- rized lost-to-follow-up for subjects who could not tive effective method in detecting precancerous le- be recalled due to inactive number or unavailable sion in the developing countries. It is both sensitive contact. Therefore, we excluded those criteria. (67-92.3%) and specific (49-99.8%).10,11 Therefore, VIA is considered as one of the most popular screening method for precancer lesion, especially in Procedure low-resource health care facility.12 History taking and physical examination were per- The management of precancerous lesion involves formed by the general practitioner in primary cryotherapy, loop electrosurgical excision proce- health care to exclude the cervicitis, nabothian cyst, dure (LEEP), laser, and knife conization.5 However, and polyp. We detected the cervical precancerous the limitation of the resource makes screening lesion by using a 5% diluted acetic acid solution. methods is not feasibly perform. Therefore, to han- The result of VIA was inspected visually with ade- dle this problem, Indonesia has "See and Treat" pro- quate light source. It was considered positive result gram, namely screening using VIA and manage- if there were acetowhite lesions on the transitional ment through cryotherapy.13 The effectivity of zone close to the squamocolumnar junction. When cryotherapy in treating the precan-cerous lesion the VIA result was positive, cryotherapy become ranges from 81.4% to 96.4% for cervical intraepi- the choice of treatment in this program. Cryo- thelial lesion (CIN) I and from 68% to 82.1% for therapy using cryoprobe was provided in two CIN II-III.14-17 The complaint after cryo-therapy pro- cycles, with 3 minutes of freeze and 5 minutes of cedure is around 5.6%, including minimal bleeding thaw in each cycle. After the process, we prescribed (1.3%). There is no major complication reported af- the analgesic and a dose of antibiotic. We also in- ter cryotherapy.15,18 formed the side effects of cryotherapy and in- struction not to have sexual intercourse for a In Indonesia, the evaluation of IVA after month. The patient was informed to come for cryotherapy in "See and Treat" program had been follow-up session in a month and six months after- done between 2004 and 2006; the effectivity reached 92%.16 However, data about the effective- wards. The one-month follow-up after cryotherapy ness of cryotherapy in Indonesia after 2006 was aimed to assess the side effect of cryotherapy, such still limited. Therefore, this study aims to describe as severe abdominal cramp, fever more than 38°C, the VIA result after cryotherapy in "See and Treat" or bloody and purulent discharge. The six-month program in Indonesia. follow-up after cryotherapy would like to assess the conversion of VIA. Patients had the conversion of VIA if the VIA result became negative on six-month METHODS follow-up. Failure of cryotherapy was divided into failure to achieve VIA conversion and suspected We used descriptive cross-sectional study design invasive cancer. Further follow-up was done to using medical records from 2010 to 2015. We observe the cause of cryotherapy failure. We took recruited by total sampling method. "See and treat" the data from the medical record; thus, we had to program was a single-visit approach program contact the subject in every missing data. Vol 4, No 4 October 2016 Efficacy and safety of cryotherapy in Jakarta 229 Calculation and data management rest of them (49 data) were lost to follow-up. Four data (2.80%) were dropped out due to missing Data were analyzed univariately by separating the data. Therefore, there were only 86 (57.34%) data conversion of VIA on the six-month follow-up into continuing to analyze. three groups, namely successful conversion, failure to convert, and suspected invasive cancer. We analyzed the data through Microsoft Excel. Demographic Characteristics

RESULTS Of 86 medical records, most of the subjects were 30-39 years old (40.7%) with the first-marriage From 2010 to 2015, there were 143 medical re- age of 20-24 years old (52.3%), having 1 to 3 cords which showed the positive VIA result. Fifty- children, and never smoke (98.84%). The number seven (39.86%) data were excluded because 8 of of subjects using hormonal and non-hormonal them (5.59%) did not do the cryotherapy and the contraceptive were similar (33.72% vs 29.07%).

Table 1. Characteristics of Subjects Variables n % Median (min­max) Age (years old) 35.0 (19.0-57.0) <20 1 1.2 20-29 18 20.9 30-39 35 40.7 40-49 28 32.6 50-59 4 4.7 First-marriage age (years old) 23.0 (16.0-33.0) <20 16 18.6 20-24 45 52.3 25-29 19 22.1 30-34 6 7.0 History of contraceptive usage None 20 23.26 Pill 15 17.44 Intrauterine device (IUD) 25 29.07 Injection 14 16.28 Implant 2 2.32 Sterile 0 0 Condom 0 0 Combination 10 11.63 Number of marriage (times) 1 85 98.84 2 1 1.16 Parity 0 5 5.81 1 27 31.40 2 26 30.23 3 21 24.42 4 6 6.98 5 1 1.16 Smoking No 85 98.84 Yes 1 1.16 Indones J 230 Lestari et al Obstet Gynecol The VIA Result Six Months after not available. Looking to the number of successful Cryotherapy cryotherapy which reached 90.7%; thus, the cryo- therapy could be reliable to convert the VIA result. "See and Treat" program required the patients to do the repeated VIA test on the six months after Subjects that failed having VIA conversion to cryotherapy to assess the conversion of VIA result. negative were 30-49-year old (75.0%) group with There were 90.70% cases of VIA positive cases the first-marriage age of 20-24 years old (87.5%), converting to negative; while, the rest of the cases history of one marriage (100%), having 2 children did not show the conversion. None of the cases (50%), and non-smoker. According to the theory, were progress to become the invasive cancer those results were similar to the risk factors of cer- (Table 2). vical cancer. Aziz MF in 2009 through their study stated that younger first-marriage age (less than Table 2. VIA Result Six Months after Cryotherapy 20 years old) had 8 times risk to be cervical can- 20 n% cer. Pramita S in 2010 concluded that number of parity was also related to the cervical cancer IVA - 78 90.70 (OR=2.59; 95% CI 1.02-6.61).21 In addition, IVA + 8 9.30 smoking could also increase the risk of squamous Suspicious of invasive cancer 0 0 cell carcinoma (RR 1.50; 95% CI 1.35-1.66).22,23 Total 86 100 Number of marriage in this study was not suitable to the theory stated that the behaviour of changing partners increased the incidence of cervical cancer DISCUSSION up to 4 times.20 However, the number of marriages "See and Treat" program aims to detect and treat cannot represent the behaviour of changing the cervical cancer from its precancerous lesion at partner. the low resource setting of primary health care Based on the history of contraception, 75% of center.13 This is a single visit approach program the subjects who used injection contraceptive that using VIA to screen and cryotherapy to treat failed to achieve the VIA conversion; while, the whether the result is positive. This program can other 25% were using pills as the method of con- decrease the lifetime risk of cervical cancer from traceptive. That result was similar to the theory 35-year-old women who have not been screened that more than five year consumption of oral con- on her entire life.16 traceptive contributed to 1.9 times risk for cervical 21 The implementation of "See and Treat" program cancer. We did not count the risk of that although involves four pillar: Firstly, the training of VIA and contraception is one of the risk factors for the VIA cryotherapy; secondly, improving the awareness of conversion. Although the cryotherapy success rate the society; thirdly, detection and treatment using in "See and Treat" program reached 90.7%, there VIA and cryotherapy; the last one is referral system were 8 people (9.3%) who did not show the VIA activation when obtaining a difficult case that has conversion to negative. Those patients were then a high progressivity to cervical cancer.13,16 The referred to Dr. Cipto Mangunkusumo Hospital focus of this study is on the third point which aims (RSCM) as the national referral hospital in Indo- to evaluate the VIA conversion after six-month of nesia for the further definitive diagnosis and ma- cryotherapy. nagement. The failure of VIA conversion can be caused by several factors, such as equipment, After six-month of cryotherapy, the conversion healthcare provider, VIA false-positive, and referral rate of VIA reached 90.7%. Similar study by Vet system factor. JNI, et al. in Jakarta, Tasikmalaya, and Bali from 2007 to 2010 also showed the similar result, Looking to equipment factor, problems that namely 92.0%.19 While it seemed that there was a could be happened came from the cessation and drop on the successful conversion rate of 1.3%, the leaking of gas flow.24 Brief survey from the difference in this proportion did not differ statisti- healthcare providers in this study showed that the cally. It was due to the high prevalence of loss to cryoprobe could sometimes stop automatically follow-up and/or incomplete data (37.07% in this before ending the two cycles of cryotherapy. study VS 52.60% in the Vet JNI, et al study).19 The Unfortunately, no further information was re- target of "See and Treat" conversion rate was still viewed and analyzed in this study. Vol 4, No 4 October 2016 Efficacy and safety of cryotherapy in Jakarta 231 Judging from the healthcare provider factor, positive result. Meanwhile, tracking through phone problems, such as technical method error, un- number or home address was difficult due to the trained healthcare provider doing the cryotherapy, lack of identity data recorded in primary health and lack of update the new methods became the care. burden for the program’s success rate because of Taking into consideration of those aspects, the failure for the ablation of the cervical precancerous failure of VIA conversion in "See and Treat" pro- lesion. Observation of the cryotherapy process was gram could be caused by lack of cryoprobe quality performed to evaluate the technique practiced by the primary healthcare provider. Examining from to ablate the precancerous lesion; lack of referral the method, the healthcare providers had used the knowledge to ensure the definitive diagnosis as same method of cryotherapy as what the guideline soon as the conversion failure was known; the recommended including 2-cycle cryotherapy with complicated referral system held in Indonesia 3 minutes of freezing and 5 minutes of thawing per contributing to the delayed colposcopy for defini- cycle. The healthcare providers were considered tive diagnosis; no policy for primary health care expert in their job as they had done this job for at workers to follow-up post referral patients; lack of least 5 years. knowledge equalization about referral system for colposcopy among regional public hospitals. In terms of VIA examination, false positive was a common interpretation. The right history taking While failure of VIA conversion was detected, we and interpretation of VIA were necessary to did not find the progressing lesion to cervical prevent over diagnosis and overtreatment of the cancer. Therefore, VIA and cryotherapy technique cervical precancerous lesion. Observing the in "See and Treat" program was considered effec- process of VIA examination, the supervisor did not tive in screening and early treatment for the cer- confirm the diagnosis. Therefore, the failure of VIA vical precancerous lesion cases. conversion could also be caused by missed We also evaluated the timing of control after diagnosis. In the primary healthcare facilities, the cryotherapy. While this study and Vet JNI, et al con- referral of patients to RSCM was a good decision sidered the first and sixth month after cryotherapy to exclude the possibility of false positive diagnosis. as the suitable control time, WHO recommended Another problem was related to the implemen- that the control should be done a year after tation of national healthcare coverage Jaminan Ke- cryotherapy. The consideration of the first-month sehatan Nasional (JKN). In JKN era, the referral sys- control was to evaluate the side effects of cryo- tem follows the level of health care. Therefore, pa- therapy; while, the consideration of the sixth- tients from the primary health care cannot be month control was to evaluate the VIA conversion. referred directly to RSCM. This problem was The cut-off of 6 months was considered as the occurred on one patient, whereas, she could not be novelty of this program in Indonesia. Prompt examined the colposcopy examination due to evaluation of the cases was expected to be able to unavailable tools in the secondary health care. minimize the incidence of cervical cancer pro- However, the difference of protocol in that gressivity. Two studies having been conducted in hospital contributed to the unsuccessful colpos- Indonesia proved the constancy of VIA conversion copy referral. in this program. Ideally, every failure of VIA conversion after The number of loss to follow-up in Indonesia cryotherapy should be referred to RSCM to be was still high. Therefore, the system of patients’ evaluated in the "See and Treat" program by identity registry, such as patients’ telephone Female Cancer Program. However, tiered referral number and the system of reminding patients, such system hampered this process. Therefore, as by contacting the patients at the time of control recommended advice was either inviting regional should be considered. doctors to participate in this program or modifying In terms of side effects, the side effect due to the rules of the referral system to suit this cryotherapy was only happened on one subject. We program. could state that cryotherapy was safe enough. This Other problems could also be seen from the side result was supported by Blumenthal, et al., Vet JNI, of the primary healthcare. We got 6 loss to follow- et al., and Fong J, et al. as their studies showed the up subjects; thus, it made a confusion for the false similar result.16,18,25 However, they did not Indones J 232 Lestari et al Obstet Gynecol mention the proportion of side effect occurrence in 3. Dhaubhadel P, Vaidya A, Choudhary P. Early detection of post cryotherapy patients. Sankaranarayanan R, et precursors of cervical cancer with cervical cytology and visual inspection of cervix with acetic Acid. JNMA. 2008; al. observed that the side effects and complications 47(170): 71-6. of cryotherapy were happened only in a small 4.Seamon LG, Tarrant RL, Fleming ST, Vanderpool RC, proportion of the population and they were not Pachtman S, Podzielinski I, et al. Cervical cancer survival for life-threatening.14 Therefore, cryotherapy was a patients referred to a tertiary care center in Kentucky. safe treatment method for precancerous lesion. Gynecol Oncol. 2011; 123(3): 565-70. However, there were still no studies that focused 5. Andrijono. Kanker serviks. Ed. 3. Jakarta: Balai Penerbit on side effects of cryotherapy. Therefore, further Fakultas Kedokteran Universitas Indonesia; 2010. studies should be held to evaluate the degree of 6. Saslow D, Runowicz CD, Solomon D, Moscicki AB, Smith RA, Eyre HJ, et al. American Cancer Society guideline for the safety from cryotherapy. early detection of cervical neoplasia and cancer. CA. 2002; 52(6): 342-62. CONCLUSION 7. World Health Organization. Comprehensive cervical cancer control. A guide to essential practice. Geneva : WHO, 2006. More than 90% (90.7%) women showing VIA- 8. Depkes RI. Skrining kanker leher rahim dengan metode positive have VIA conversion after 6 months of inspeksi visual dengan asam asetat (IVA). Jakarta: Depkes, cryotherapy. We do not find the progression to 2008. invasive cancer in 6 months. Therefore, cryo- 9. Bharani B, Phatak S. Acetic acid visualization of the cervix an alternative to colposcopy in evaluation of cervix at risk. therapy in this program is effective in the early J Obstet Gynecol Ind. 2005; 55: 530. management cervical precancerous lesion. 10. Ocviyanti D. Tes Pap, tes HPV dan servikografi sebagai pe- meriksaan triase untuk tes IVA positif: upaya tindak lanjut deteksi dini kanker serviks pada fasilitas kesehatan dengan RECOMMENDATION sumber daya terbatas beserta analisis sederhana efektivitas Some recommendations for the next study consist biayanya. Maj Obstet Ginekol Indones. 2007; 31(4): 201-11. of the need to evaluate "See and Treat" program 11. Sankaranarayanan R, Gaffikin L, Jacob M, Sellors J, Robles S. A critical assessment of screening methods for cervical from other aspects to further increasing the neoplasia. Int J Gynaecol Obstet. 2005; 89 Suppl 2: S4-S12. coverage rate; the need of further assessment 12. Nuranna L. Penanggulangan kanker serviks yang sahih dan about the aetiology of VIA-conversion failure, such andal dengan model proaktif-VO (proaktif, koordinatif as the false-positive of VIA result, the quality of dengan skrining IVA dan terapi krio) [Disertasi]. 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